Nixon was born in Durham, North Carolina and attended New Hanover High School in Wilmington, North Carolina. As a senior, he was named the State Player of the Year in both football and baseball. In football, as a senior, he broke school passing records held by former National Football League quarterbacks Sonny Jurgensen and Roman Gabriel. Nixon was slated to join the North Carolina State football team on a scholarship before being drafted by the Boston Red Sox. In baseball, as a senior, he was named the Baseball America High School Player of the Year and the State Player of the Year, and helped lead his team to the State 4A title, and finished his senior season with a .512 batting average, 12 home runs and a state-record 56 RBI, and pitched 40 innings with a 12–0 record and a 0.40 ERA.
Nixon was drafted by the Red Sox in the 1st round of the 1993 Major League Baseball Draft, and was the seventh pick overall. Nixon split the 1994-1998 seasons between several A, AA, and AAA minor league teams, with two brief stints with the Red Sox on the major league level in 1996 and 1998.
Nixon's first full season in the majors was in 1999, when he played in 124 games and hit .270 with 15 home runs and 52 RBIs. Nixon came in 9th place in Rookie of the Year voting with just a single vote point (Carlos Beltrán of the Kansas City Royals won the award by a landslide).
Nixon quickly became a fan favorite for his scrappy, enthusiastic gameplay. Nixon served as the considered inspiration for the expression "Boston Dirt Dogs." The signature is that of a "scrapper," which is a player who hustles and can usually gets his uniform dirty during games.
After a decent 2000 season, Nixon came back and produced career-highs (at the time) during the 2001 season with a .280 batting average, 27 home runs, and 88 RBIs.
The 2002 season was also a good one for Nixon, wherein he posted career-bests in doubles (36) and RBIs (94). On May 5, 2002, Trot Nixon threw his bat in the direction of Tampa Bay Devil Rays pitcher Ryan Rupe, pretending that the bat slipped out of his hands while swinging. In response, Bob Watson, the Major League Baseball vice president in charge of discipline, fined him $2,000 and suspended him four games.
Nixon had the best year of his career in 2003, batting .306 with 28 home runs and 87 RBIs. On October 4, 2003, in Game 3 of the American League Division Series, Nixon had the most prominent moment of his career. Nixon was called from the bench as a pinch hitter in the bottom of the 11th. With the Red Sox facing elimination, Nixon lined a two-run homer over the center field wall for a 3–1 Boston victory. The Red Sox would go on to win the next two games, stunning the Oakland Athletics with a 3-2 series win, advancing to the American League Championship Series against the New York Yankees. The Red Sox would lose this series in a heartbreaking Game 7 loss despite the fact Nixon was a major contributor for the Sox, batting .333 (8 for 24) with 3 home runs and 5 RBIs in the series.
During the 2004 season, Nixon was unavailable for several months due to a herniated disc and a tight thigh muscle. Upon his return, he generally worked as the starting right fielder throughout the regular and post-season. In the deciding game of the 2004 World Series, Nixon hit a two-out, two-run double off the right field wall at Busch Stadium in St. Louis in the top of the third inning to give Boston a 3–0 lead. Those were the last runs scored by either team in that game as the Red Sox swept the Cardinals for the team's first World Series title in 86 years. For the series, Nixon batted .357 (5 for 14) with 3 doubles and 3 RBIs.
Nixon also endeared himself to Sox fans by briefly wearing a mohawk hairstyle, one of the many unconventional and bizarre hairstyles sported by the Red Sox over the course of the 2004 season.
Loved by Boston's fans, Nixon is known for an extremely volatile temper and steadfast dedication to his teammates. In August 2005, while officially on the disabled list, Nixon remained in uniform and in the dugout with the rest of the team during the game. When teammate Gabe Kapler (who often acted as Nixon's right field replacement) hit a long fly ball off of the Green Monster, the umpires ruled it a double. Nixon leapt off the bench and argued with such passion that Kapler's hit had been a home run (television replays confirmed that the hit had landed above the home run line, and thus should have been ruled a two-run homer) that he was ejected from the game.
On October 1, 2006, with two outs in the fifth inning of the final game of the season, manager Terry Francona replaced Nixon in right field with rookie David Murphy. Knowing Nixon might be playing his final game with the Sox, the fans delivered a grateful ovation to Nixon as he ran off the field. Said Nixon, when asked if it was difficult playing what may have been his last game for the Red Sox:
There were a couple of times—my first at-bat and coming out of the game. It really was, because this is the only organization I've ever known. There was [sic] definitely a couple of times out there that I did want to break down. I really did care about this organization. I did care about this town. I think this town has been unbelievable for my family and me. Absolutely unbelievable. I think there's a lot of guys in this organization who feel the same way.
Following the 2006 season, Nixon was not offered salary arbitration by the Red Sox as the team pursued and eventually signed free agent J. D. Drew, coupled with the fact that Boston had a fourth outfielder, Wily Mo Peña, on the roster.
In 2010, Red Sox manager Terry Francona compared rookie Red Sox outfielder Ryan Kalish's intensity and aggressiveness to that of Nixon.
In January 2007, Nixon signed a one-year, $3 million contract with the Cleveland Indians. Instead of wearing number 7 as he had in Boston, Nixon chose number 33. The decision was made in part by his son Chase, based on the fact that Nixon turned 33 years old that April.
In February 2008, he signed a minor league contract with an invitation to spring training with the Arizona Diamondbacks and was subsequently sent to their Triple-A affiliate the Tucson Sidewinders.
On June 13, 2008, Nixon was acquired by the New York Mets from the Diamondbacks for cash considerations and a player to be named later. The Mets acquired him to replace injured outfielder Moisés Alou. He was added to the Mets roster on June 15, replacing outfielder Chris Aguila who was designated for assignment. The same day he was activated, Nixon started in right field against the Texas Rangers. However, he finished the season on the disabled list.
On December 18, 2008, he signed a minor league contract with the Milwaukee Brewers. He was put onto the inactive roster. After his release from the Brewers in March 2009, Nixon retired from baseball.
Nixon is married to his wife, Kathryn, with whom he has two sons, Chase (born September 11, 2001) and Luke (born October 1, 2004). Nixon was flying back to Boston to be at Chase's birth when all air traffic was halted due to the September 11 attacks on the Twin World Trade Center Towers in New York City. His father lives in Wilmington, North Carolina, and his grandmother and cousins live in Hertford, North Carolina.
Nixon is a Christian, and was known to share his faith in the clubhouse with his teammates.
Nixon is also co-host of "The 5th Quarter" Friday night high school football highlight show on WWAY-TV.
Nixon and his family reside in Wilmington, NC.