Huff attended Vernon College and the University of Miami, where he finished his career second in school batting average. He was drafted by the Devil Rays in the sixth round in 1998. After a couple years in the minor leagues, he debuted with the Devil Rays in 2000. His first full season in the majors came in 2001. In 2002, he finished tenth in the American League (AL) in batting average. He set a career high in 2003 with 34 home runs and batted .311 with 107 runs batted in (RBI). Next season, he batted .297 with 24 home runs and 104 RBI. In 2005, he was placed on the disabled list for the first time in his career, but he batted .261 with 22 home runs and 92 RBI. During the 2006 season, he was traded to the Astros.
In 2007, Huff signed a three-year contract with the Orioles. He hit 15 home runs his first season with the Orioles, his lowest total since 2001. In 2008, he won the Silver Slugger Award for the designated hitter position after batting .304 with 32 home runs and a career-high 108 RBI. During the 2009 season, he was traded to the Tigers. He became a free agent after the season and signed a one-year deal with the Giants. He batted .290 with 26 home runs in 2010, reached the playoffs for the first time, and won his first World Series. He signed a two-year deal with the Giants in 2011 and hit 12 home runs, his lowest total since 2001. In 2012, he was used mostly as a pinch hitter and appeared in a career-low 52 games but won his second World Series with the Giants.
On January 4, 2014, Huff officially announced his retirement from baseball and took a position as a baseball color commentator.
Although he was born in Marion, Ohio, Huff grew up in Mineral Wells, Texas. When he was six years old, his father, Aubrey II, was killed as an innocent bystander in a domestic dispute while working as an electrician. That left Huff's mother Fonda in charge of raising him and his sister Angela. Growing up, Huff regularly practiced baseball in his yard, which had a batting cage with lights and a pitching machine. He said, "[My mother bought] it more to keep me out of trouble." He grew up rooting for the Texas Rangers and frequently attended their games. One of his favorite players was Nolan Ryan. Huff initially attended Mineral Wells High School but then transferred to Brewer High School when his family moved to Fort Worth. Although he was selected to the All-District baseball team in high school, he was better known as a basketball player. He graduated in 1995.
Huff attended Vernon College for two years and was named the Most Valuable Player (MVP) of its baseball team in 1996. Huff transferred to the University of Miami for his final two years of college baseball. As a junior, he tied team single-game records for runs in a game (five against Harvard University on March 28) and most doubles in a game (four on May 16 against Georgia Tech).
As a senior, Huff hit for a .412 batting average, the fourth highest single-season average in school history. His .768 slugging percentage is the second highest in school history. He also hit 21 home runs (fifth in school history) and a school record of 95 runs batted in (RBI). Baseball America, The Sporting News, and the National Collegiate Baseball Writers Association named him a first-team All-American.
Huff finished his college career with a .400 batting average (second in school history) and a .719 slugging percentage (third in school history). In 2009, he was inducted into the University of Miami Sports Hall of Fame.
Huff was the Tampa Bay Devil Rays' fifth-round selection in the 1998 Major League Baseball (MLB) draft. He spent 1998 with the Charleston RiverDogs of the single-A South Atlantic League, where he batted .321 with 85 hits, 19 doubles, 13 home runs, and 54 RBI in 69 games.
In 1999, Huff played for the Orlando Rays of the double-A Southern League and was named a Southern League postseason All-Star. In 133 games with the Rays (tied with three players for fourth in the league behind Brady Clark's 138, Brent Abernathy's 136, and Kurt Airoso's 134), Huff batted .301 (eighth) with 148 hits (fourth, behind Abernathy's 168, Clark's 165, and Tim Giles's 157), 40 doubles (third, behind Scott Vieira's 44 and Abernathy's 42), 22 home runs (tied with John Curl for second behind Javier Cardona's 26), and 78 RBI (tied with Bry Nelson for ninth in the league).
Huff began 2000 with the Durham Bulls of the triple-A International League. In 108 games, he batted .316 (fifth) with 129 hits, 36 doubles (fourth, behind Clark's 41, Ryan Jackson's 38, and José Fernández's 37), 20 home runs, and 76 RBI. He was named the International League Rookie of the Year and was named to the postseason All-Star team.
Huff was called up by the Devil Rays at the beginning of August to be the starting third baseman after Vinny Castilla suffered an injury. He had an RBI in his debut on August 2, a 5–3 loss to the Cleveland Indians. Two days later, he got his first career hit against José Mercedes in a 10–9 loss to the Baltimore Orioles. On August 10, he had a season-high three RBI by hitting his first career home run, a game-winning three-run hit against Jason Ryan in a 10–4 victory over the Minnesota Twins. In 39 games, Huff hit .287 with 35 hits, seven doubles, four home runs, and 14 RBI.
Huff began the 2001 season with Durham but was called up on April 13 when Ariel Prieto was sent to the minors. He became the starting third baseman on May 11 when Castilla was released. On June 29, he had three RBI in a 7–5 loss to the New York Yankees. Huff was moved from third base to first base on August 6 following an injury to Steve Cox. After batting .243 with 6 home runs and 33 RBI in his first 92 games, he was optioned to Durham on August 23 when Cox came off the disabled list (DL). In September, he was called up to replace Greg Vaughn as the Devil Rays' designated hitter (DH). On September 19, he had three hits and five RBI, including a game-winning single against David Cone, in a 12–2 victory over the Boston Red Sox. He finished the season batting .248 with 102 hits, 25 doubles, eight home runs, and 45 RBI in 111 games. In 17 games at Durham, he batted .288 with 19 hits, six doubles, three home runs, and 10 RBI.
Huff missed the first month of 2002 with a broken cheekbone and began the season in the minor leagues before getting called up on May 28 to replace the struggling Jason Tyner on the roster. He started for the rest of the season as a first baseman, a third baseman, or a DH. On June 9, he hit a three-run home run against Bobby Jones in a 9–6 loss to the San Diego Padres. He hit a game-winning two-run home run against Félix Heredia on June 26 in a 4–2 victory over the Toronto Blue Jays. On July 19, he had four hits, including a home run against Esteban Loaiza, and three RBI in an 11–8 loss to the Blue Jays. On August 5, his three-run home run against Jon Garland accounted for all of the Devil Rays' scoring in a 4–3 loss to the Chicago White Sox. On August 18, he had three hits and three RBI, including a home run against Jeff Suppan, as the Devil Rays defeated the Kansas City Royals 8–6. He had a 17-game hitting streak from August 23 to September 10, the second-longest streak in franchise history at the time (behind Quinton McCracken's 18-game streak in 1998) and as of 2012 the third-longest (behind Jason Bartlett's 19-game streak in 2009). In 113 games, Huff finished tenth in the American League (AL) with a .313 batting average and had 142 hits, 25 doubles, 23 home runs, and 59 RBI. He led the Devil Rays in home runs, marking the first time a player led his team in home runs after starting the season in the minors since 1996, when Tony Clark led the Detroit Tigers. In 32 games with Durham, he batted .325 with 41 hits, nine doubles, three home runs, and 20 RBI.
On April 26, 2003, Huff had four hits in a 10–7 victory over the Baltimore Orioles. After playing mostly first and third base in April, he took over from George Lombard as the Devil Rays' right fielder for the remainder of the season on April 29. On May 3, he had the first multihomer game of his career by hitting two two-run home runs against Adam Bernero in an 8–6 victory over the Tigers. He had four hits on June 4 in a 5–2 victory over the Chicago Cubs. In the first game of a doubleheader on June 17, Huff had four RBI in an 11–2 victory over the Yankees. On July 2, he had all four Devil Rays' RBI and hit a three-run home run against Pedro Martínez in a 5–4 loss to the Red Sox. On September 3, he hit a three-run home run against Freddy García and had four RBI in a 7–0 victory over the Seattle Mariners. On September 6, he stole home plate in a 7–4 victory over the Oakland Athletics. On September 23, he had four hits and hit a home run against Josh Towers in an 8–5 loss to the Blue Jays. In 162 games (tied for second in the AL with Miguel Tejada behind Hideki Matsui's 163), he batted .311 (ninth) with 47 doubles (third behind Garret Anderson's and Vernon Wells's 49), 34 home runs (ninth), and 107 RBI (tied for eighth with Jason Giambi). Huff's single-season totals in hits, doubles, home runs, and RBI have been matched by eleven players in major league history as of 2012. He was tied for 24th in AL Most Valuable Player (MVP) voting along with Esteban Loaiza and Jason Varitek. Defensively, he tied with Tim Salmon for the lead in errors by AL right fielders with six.
In 2004, Huff spent most of the season playing third base. On May 12, he had five RBI, including a three-run home run against Chan Ho Park, in a 9–8 victory over the Texas Rangers. On May 28, he had four hits, three runs scored, and two RBI including a home run against Javier Vázquez in a 7–5 victory over the Yankees. Two days later, he hit two home runs against Jon Lieber and had three hits and RBI in a 7–6 victory over the Yankees. Four days later, he hit a game-winning three-run home run against Johan Santana in a 5–2 victory over the Twins. On June 15, he hit a game-winning three-run home run against Brian Lawrence in a 5–2 victory over the San Diego Padres. On July 2, he had three RBI and hit a game-winning two-run home run against Carl Pavano in a 4–2 victory over the Florida Marlins. He saw a streak of 398 consecutive games played snapped on August 22 when he was forced to miss a game with a minor back injury. He told reporters afterwards, "You guys care more about the streak than I do." On August 27, he had four hits in an 8–7 loss to the Athletics. Four days later, he had three hits, two home runs, and four RBI in a 12-inning, 10–6 loss to the Orioles. He had four hits on September 23 in a 7–3 loss to the Yankees. Huff finished the season batting .297 with 178 hits, 27 doubles, 29 home runs, and 104 RBI in 157 games. His average, home runs, and RBI were the highest totals among Devil Rays' players.
In 2005, Huff spent most of the year in right field. On April 18, Huff had four RBI and hit the 100th home run of his career, a three-run shot against Jaret Wright in a 19–8 loss to the Yankees. He had three hits and four RBI, including a game-winning three-run home run against Aaron Sele, on June 3 in a 6–1 victory over the Mariners. After hitting 5 home runs in the first three months, Huff hit 17 home runs through the rest of the season. On July 22, he hit the first grand slam of his career, a game-winning home run against Bruce Chen in a 7–5 victory over the Orioles. Three days later, he had a walk-off double against Curt Schilling in a 10-inning, 4–3 victory over the Red Sox. The next day, he hit a grand slam against Chad Bradford in a 10–8 loss to the Red Sox. Three days later, he had two hits and four RBI, including a three-run home run against D. J. Carrasco in a 6–3 victory over the Royals. He was named the AL Player of the Week from July 25 to 31 after he batted .409 with two home runs and 10 RBI. On August 28, Huff drove in all the runs for the Devil Rays with a two-run home run against Jarrod Washburn in a 2–1 victory over the Los Angeles Angels of Anaheim. On September 30, he had two hits and hit a three-run home run against John Maine in a 7–6 loss to the Orioles. In 148 games, Huff batted .261 with 150 hits, 26 doubles, 22 home runs, and 92 RBI.
For 2006, Huff was moved back to third base. He was placed on the disabled list for the first time in his career on April 12 with a sprained left knee suffered in a collision with Nick Green the day before. On May 4, he was activated from the DL. On May 19, he hit his first career walk-off home run against Yusmeiro Petit in a 10-inning, 5–4 win over the Marlins. He had three hits and three RBI on June 22, including a game-winning two-run home run against Édgar González in a 4–1 victory over the Arizona Diamondbacks. On July 9, he hit a three-run home run against Kris Wilson in a 6–5 victory over the Yankees. Through July 9, Huff batted .283 with 65 hits, 15 doubles, 8 home runs, and 28 RBI in 63 games.
On July 12, 2006, the Houston Astros acquired Huff from Tampa Bay for minor leaguers Mitch Talbot and Ben Zobrist. Huff was used at third base for the Astros until August 1, when he was moved to right field following regular third baseman Morgan Ensberg's return from the DL. In his debut with the Astros on July 13, the first game after the All-Star break, Huff had two hits, including a three-run home run against Randy Messenger in a 5–1 victory over the Marlins. On August 9, he had three hits, two home runs, and six RBI in a 14–1 victory over the Pittsburgh Pirates. He hit a game-winning home run against José Capellán on September 8 in a 4–3 victory over the Milwaukee Brewers. In 68 games with Houston, Huff batted .250 with 56 hits, 10 doubles, 13 home runs, and 38 RBI. He combined to bat .267 with 121 hits, 25 doubles, 21 home runs, and 66 RBI in 131 games in 2006. On October 31, he filed for free agency.
On January 3, 2007, Huff officially signed a 3-year $20 million contract with the Baltimore Orioles. He began the year getting most of the starts at first base, but in mid-May he became the Orioles regular DH as Kevin Millar was moved to first base. On May 9, he hit a walk-off home run against Brian Stokes to account for the game's only scoring in a 10-inning, 1–0 win over Tampa Bay. In a 9–7 loss to the Angels on June 29, he hit for the cycle and got his 1000th hit and 200th double (both against Kelvim Escobar). He is one of four Orioles to hit for the cycle (along with Brooks Robinson, Cal Ripken, Jr., and Félix Pie) and the first player to do so at Oriole Park at Camden Yards. On August 3, his three-run home run against James Shields accounted for all the Orioles' runs in a 3–1 victory over Tampa Bay. On August 14, Huff had two hits and five RBI, including a grand slam against Jeff Karstens in a 12–0 victory over the Yankees. He had four hits on September 15 in an 8–3 loss to the Blue Jays. In 151 games, Huff batted .280 with 154 hits, 34 doubles, 15 home runs, and 72 RBI.
Before the 2008 season, Huff switched his uniform number from 19 to 17 in honor of his former teammate Joe Kennedy, who died during the offseason. He angered fans in the offseason when he called Baltimore a "horse----" town when compared to Tampa, but he regained fan support by the end of the year by posting one of his best seasons. He was the Orioles' designated hitter for most of the season, although he was moved to third base at the end of August following an injury to Melvin Mora. On April 2, he hit a two-run home run against Matt Garza and a game-winning two-run double against Al Reyes in a 9–6 victory over Tampa Bay. On April 8, he had four hits and four RBI in an 8–1 victory over the Rangers. On July 3, he had three hits, three RBI, and two home runs against Kyle Davies in a 10–7 loss to the Royals. He was named AL Player of the Week from June 30 to July 6 after hitting .345 with three home runs and nine RBIs. On August 27, he had three hits and three RBI, including a two-run home run against Lance Broadway in an 11–3 victory over the White Sox. Two days later, he had two hits, including a three-run home run against Andy Sonnanstine in a 10–9 loss to Tampa Bay. He was named the Player of the Week again from August 25–31 after batting .478 with two home runs and seven RBI. He hit a grand slam against Juan Rincón on September 8 in a 14–3 victory over Cleveland. In 154 games, Huff batted .304 with 182 hits (tied with Nick Markakis for 10th in the league), 48 doubles (tied with Markakis for third in the league behind Dustin Pedroia's 54 and Brian Roberts's 51), 33 home runs (tied for eighth with Jason Giambi and Josh Hamilton), and 108 RBI (sixth). He finished 16th in AL MVP voting and was named "Most Valuable Oriole" by Baltimore sportswriters. He won the Silver Slugger Award for DH and the Edgar Martínez Award, becoming the first Oriole to win the award since Tommy Davis in 1974.
Huff moved to first base in 2009 following the departure of Millar. On April 13, he had four hits and three RBI in a 10–9 victory over Texas. On April 21, he hit two home runs and had four RBI in a 10–3 victory over the White Sox. He hit a game-winning three-run home run against Phil Hughes on May 9 in a 12–5 victory over the Yankees. The next day, he hit a three-run home run against Joba Chamberlain in a 5–3 loss to the Yankees. On June 17, he had three RBI, including a game-winning two-run home run against Pedro Feliciano in a 6–4 victory over the New York Mets. Through August 17, Huff batted .253 with 109 hits, 24 doubles, 13 home runs, and 72 RBI in 110 games.
On August 17, 2009, Huff cleared waivers and was traded to the Detroit Tigers in exchange for pitching prospect Brett Jacobson. He began his time with the Tigers as the team's DH, but in September he only played against right-handed pitchers as Marcus Thames began playing against left-handed pitchers. He hit his first career pinch-hit home run against Jason Frasor on September 14, a game-tying three-run hit in a 10-inning, 6–5 victory over Toronto. In 40 games with the Tigers, Huff batted .189 with 20 hits, six doubles, two home runs, and 13 RBI. His season totals were a .241 batting average, 129 hits, 30 doubles, 15 home runs, and 85 RBI in 150 games. Following the season, Huff filed for free agency.
On January 13, 2010, Huff signed a one-year, $3 million contract with the San Francisco Giants. He spent most of the season playing first base for the Giants, although he played left field and right field when Buster Posey played first base from May 29 – June 30 and Travis Ishikawa made most of the starts at first base from July 3 – August 14. On April 14, Huff hit his first career inside-the-park home run (his first home run with the Giants), a game-winning hit against Charlie Morton in a 6–0 victory over the Pirates. On June 4, he hit a game-winning two-run home run against Zach Duke in a 6–4 victory over Pittsburgh. He hit two two-run home runs on June 13, including a game-winning home run against Vin Mazzaro in a 6–2 victory over Oakland. On July 8, he had four RBI and a two-run home run against Manny Parra in a 9–3 victory over the Milwaukee Brewers. He hit a game-winning two-run home run against Blake Hawksworth on August 20 in a 6–3 victory over the St. Louis Cardinals. On August 28, he got his 1,500th career hit against Alex Sanabia in a 10-inning, 10–9 victory over the Marlins. In 157 games, Huff batted .290 with 165 hits, 35 doubles, 26 home runs, and 86 RBI while scoring 100 runs (tied for seventh in the league with Brandon Phillips, Martín Prado, and Dan Uggla) for the first time in his career. Huff finished seventh in the voting for the NL MVP award.
Huff, in the 11th year of his career, reached the playoffs for the first time as the Giants won the NL West. In Game 4 of the NL Division Series (NLDS) against the Atlanta Braves, he had a ninth-inning, two-out, game-tying RBI single against Mike Dunn in a 3–2 Giants' victory. He batted .267 with four hits and one RBI in the series as the Giants defeated the Braves in four games. In Game 4 of the NL Championship Series (NLCS) against the Philadelphia Phillies, on October 20, he had three hits, two runs scored, and an RBI in a 6–5 Giants' victory. He batted .250 with six hits and three RBI in the series as the Giants defeated the Phillies in six games. In Game 1 of the World Series against the Texas Rangers, on October 27, he had three hits and an RBI in an 11–7 Giants' victory. In Game 4 of the series on October 31, he hit a game-winning two-run home run against Tommy Hunter in a 4–0 Giants' victory. He batted .294 with five hits, a home run, and four RBI in the series, winning his first World Series as the Giants defeated the Rangers in five games to win their first World Series in 56 years.
Huff filed for free agency after the 2010 season, but on November 23, 2010, he re-signed a $22 million contract with the Giants for two years with a club option for 2013. Coming off the team's 2010 World Series success and his new contract, Huff arrived at 2011 spring training out of shape. He began 2011 in right field due to an injury to Cody Ross, but he returned to first base when Ross was activated from the disabled list on April 20. He drew a pinch-hit, game-winning, bases loaded walk on April 30 against John Lannan in a 2–1 victory over the Washington Nationals. Three days later, he hit a game-winning home run against Taylor Buchholz in a 10-inning, 7–6 victory over the New York Mets. He had a walk-off RBI single against Brian Fuentes on May 20 in a 10-inning, 2–1 victory over Oakland. On June 2, his wife's birthday, Huff hit three home runs and drove in a career-high six runs in the Giants' 12–7 win over the St. Louis Cardinals. He said after the game, "[My wife] wanted me to hit her a homer. I hit three. Brownie points." Those home runs accounted for a quarter of his season total, as his overall production dropped from the previous season. Compared to 2010, his batting average dropped 44 points, his homers fell from 26 to 12, and his walks went from 83 to 47 as he grew impatient. His On-base plus slugging (OPS) dropped 215 points to .676, last among Major League first baseman in 2011. Giants' manager Bruce Bochy said, "[Huff's] struggles helped cause our struggles"; the Giants failed to return to the playoffs in 2011.
In 2012 spring training, Huff competed with Brandon Belt and Brett Pill for the Giants' first base job. Belt won the job, and Huff opened the season as the Giants' left fielder. He had two hits and three RBI on April 13, including a two-run home run against Joel Hanrahan in a 5–0 victory over Pittsburgh. On April 21, because the Giants did not have any infielders available, Huff was positioned at second base for the first time in his career in the ninth inning of a tied game against the Mets. He failed to cover second base in a potential double play situation, and the Mets went on to win the first game of the doubleheader 5–4. After the game, on April 25, Huff was placed on the 15-day disabled list with anxiety issues.
He returned from the DL on May 7 but was used mainly as a pinch hitter for the rest of the season. On June 15, he was placed on the DL with a sprained right knee that he suffered jumping over a dugout railing to celebrate Matt Cain's perfect game. He returned from the DL on July 28 but was placed on it four days later with right knee tendinitis, which kept him out until August 31. In 52 games, Huff batted .192 with 15 hits, four doubles, one home run, and seven RBI. In the playoffs, Huff was used exclusively as a pinch hitter. In 10 games, he had one hit in nine at-bats but won his second career World Series as the Giants swept the Tigers in four games. On November 1, Huff's $10 million club option was declined, making him a free agent. He instead earned a $2 million buyout.
Huff ranks among the top ten in several career and single-season records in the history of the Tampa Bay Rays (Devil Rays from 1998–2007) as of 2012. Through 2012, he ranks third behind Carl Crawford and B. J. Upton in games played (799), at bats (3,028), plate appearances (3,322), hits (870), and doubles (172). His .287 batting average ranks fourth (behind Crawford's .296, Fred McGriff's .291, and Jason Bartlett's .288), his 128 home runs rank second (behind Carlos Peña's 161), his 449 RBI rank third (behind Crawford's 592 and Peña's 458), and his 400 runs scored rank fifth. He and Delmon Young are the only Devil Rays to appear in 162 games in a season. He holds Devil Rays' record for hits in a season and doubles in a season, both set in 2003. His batting averages in 2002 and 2003 rank sixth and seventh, respectively; his home run totals in 2003 and 2004 are tied for third (with Jose Canseco's 1999 total behind two of Peña's totals) and ninth, respectively; and his RBI totals in 2003 and 2004 are fourth and tied for sixth (with Evan Longoria's 2010 total and McGriff's 1999 total), respectively.
Through the 2012 season, Huff had hit 242 career home runs, tying him for 217th all-time with Dusty Baker, Sal Bando, Wally Berger, Roy Campanella, and J. D. Drew. In addition to being used as a designated hitter, he has played at five different positions in his career: first base, third base, left field, right field, and second base.
On January 27, 2007, Huff married Barbara "Baubi" Heaton. The couple has two sons: Jayce (born September 4, 2008) and Jagger (born September 15, 2010). During Huff's playing days, they resided in Tampa, Florida, in the off-season. Baubi Huff filed for divorce on January 31, 2012, but the two later reconciled. Huff's mother lives in Largo, Florida, where she teaches math. His sister, Angela, is a store manager there. As of 2015, Huff and his family reside in Carmel Valley, San Diego.
Huff has several tattoos. A noted Transformers fan, he has the logos of the Autobots and Decepticons tattooed on his shoulder blades. On his left shoulder, he also has a tattoo of a guitar with his father's name under it in memory of his father.
During the Giants' 2010 playoff race and postseason, Huff became known for wearing a red "rally thong", which he joked would help the team win. When he was slumping in 2011, fans sent him thongs throughout the season in hopes of improving his performance.
On January 4, 2014, Huff officially announced his retirement from baseball and took a position as a baseball color commentator for the Pac-12 Network. On March 31, 2014, Huff started co-hosting a morning radio show on Bay Area sports radio station 95.7 The Game with Chris Townsend and Ric Bucher titled Bucher, Towny and Huff. Huff left the show in August 2014.
Huff was an assistant baseball coach at Canyon Crest Academy in San Diego, California in 2015. In late 2015, Huff announced he was attempting a comeback three years after playing his final Major League game. In February 2017, he released a book, co-written by Stephen Cassar, entitled Baseball Junkie, in which he opens up about his "battle with anxiety and the pressure of playing in the Major Leagues".