Span bats and throws left-handed and is known as one of the premier leadoff hitters in baseball due to his exceptional on-base percentage. He is also one of the top defenders in the MLB for his ability to make difficult catches.
Span was selected by the Twins with the 20th overall pick in the 2002 Major League Baseball draft from Tampa Catholic High School. Span turned down just over $2 million from the Colorado Rockies in a predraft deal (who instead drafted Jeff Francis with the eighth pick) and his fall to the 20th pick cost himself around $800,000. Following his selection, Span signed with the Twins on August 15, 2002 which caused him to miss all of the 2002 minor league season. He started his minor league career in 2003 at Elizabethton, the Twins rookie-league affiliate. In 2004, Span was promoted first to the Gulf Coast League Twins in Fort Myers, Florida and, after only appearing in 5 games, for the Quad Cities of the Low Single A Midwest League. In 2005, he was promoted to Fort Myers Miracle, the Twins Advanced A affiliate, and then to the New Britain Rock Cats, the Twins Double-A affiliate. In 2006, Span returned to the Rock Cats, but was promoted Triple-A Rochester Red Wings in 2007.
Throughout the 2008 spring training, Span was competing with Carlos Gómez to be the Twins' starting center fielder, but ultimately lost out to Gomez and was outrighted to AAA. However, on April 6, Michael Cuddyer was placed on the 15-day disabled list and Span was called up to make his Major League debut against the Kansas City Royals. Span failed to impress the Twins (hitting .258/.324/.258) and was sent back down to AAA. However, He got hot over the next 40 games in AAA (.340/.434/.481) and was recalled to the Twins where he spent the rest of 2008 season. Span's 2008 season totals were .294/.387/.432 with 6 HR, 47 RBI, and 7 triples in 93 games. Span was chosen to play in the 2008 Beijing Olympics but because he had been promoted, he was forced to skip the Olympics.
In 2009, Span, unlike in 2008, got the nod to start as a left fielder. He also played center field and right field throughout the season. His 2009 stats showed some improvement from 2008, hitting .311/.392/.415 with 8 HR, 68 RBI, and 10 triples in 145 games. He also stole bases 23 times while getting caught 10 times. Span earned the odd distinction of becoming the player to hit both the first regular and post season hits at Yankee Stadium in 2009.
On March 13, 2010, Span made public a five-year deal worth $16.5 million with the Minnesota Twins that included an option for the 2015 season worth $9 million with a $500,000 buyout. This contract effectively bought out all of Span's arbitration years but did not go beyond his available free agency. On March 31, he unintentionally hit his mother, who was sitting in the stands, with a foul ball. On April 2, 2010, Span collected the first hit (a triple) and the first home run in the Twins' new ballpark Target Field in an exhibition game against the St. Louis Cardinals.
On June 29, Denard Span tied the modern-day Major League Baseball record by hitting three triples in one game when he did so against the Detroit Tigers in an 11-4 victory. He became the 29th player since 1900 to accomplish this feat, the second Minnesota Twin (after Ken Landreaux in 1980), and the first player since the Atlanta Brave Rafael Furcal performed the feat on April 21, 2002. His night also included a single and five runs batted in.
Overall, Span hit .284/.357/.389 in his Minnesota career, with 254 walks and 321 strikeouts in 2354 at-bats and stole 90 bases in 118 attempts. Adding his strong defense gives him an overall wins above replacement of 15.9. He also became the first ever player on the 7-Day Disabled List in 2012.
After being tied with the Nationals in trade rumors as far back as 2011, the Twins finally traded Span to the team on November 29, 2012 for Washington's 2011 first round pick (23rd overall), starting pitcher Alex Meyer. After the trade, Span became the team's starting center fielder, moving 2012 NL Rookie of the Year Bryce Harper to left field. During the 2013 season, Span set a personal and league high with a 29-game hit streak (besting the previous 2013 season high of 27 games set by former Twins teammate Michael Cuddyer). The streak ended on September 19 following an 0-4 performance against the Miami Marlins. During the streak, Span raised his season average from .258 to .281 (46 for 128) while hitting 2 HR, 9 RBI, and scoring 21 runs.
On December 3, 2014, Span underwent a sports hernia surgery. He claimed that he suffered this injury toward the end of the 2014 season but didn’t miss any games. Recovery time required 6 weeks, giving him enough time to be ready for 2015 Spring training. During March 2015, Span underwent core muscle surgery. He began the 2015 season on the 15-day disabled list and made his season debut on April 19, 2015.
On January 7, 2016, Span signed a three-year, $31 million, contract with the San Francisco Giants that included a mutual option for 2019 and $5 million in performance bonuses.
On June 13, 2016 at AT&T Park, Span became the first San Francisco Giant to hit a leadoff splash hit home run in the first inning into McCovey Cove and joined the San Diego Padres' Brian Giles (2008) as the only two players in the history of the ballpark to accomplish the feat.