He graduated from Harry P. Harding High School (now Harding University High School) in Charlotte, North Carolina in 1990, where he played baseball and football. He was on the state select baseball team and was an honorable mention All-American defensive back. He did not attend college as he began playing minor league baseball with the Gulf Coast White Sox. Ray Durham was originally a 5th round pick by the Chicago White Sox in 1990. Durham has not played since the 2008 season and resides in California with his wife Regina and three of their four children.
Durham was a member of the Chicago White Sox from 1995 to 2002. Durham was a leadoff hitter during these years of his career. Durham established himself as one of baseball's better leadoff hitters with above league average on-base percentages and averaging well over 20 stolen bases and 10 home runs per season. His performance from 2000 to 2002 was exceptional. By posting at least 15 home runs with 100 runs, 20 steals, a .450 slugging percentage and 65 RBIs in three consecutive seasons, Durham became just the 10th player in baseball history to accomplish such a feat. Durham is in great company, with the list including Hall of Famers Hank Aaron, Willie Mays, and Joe Morgan, as well as Barry Bonds and Alex Rodriguez. Durham left Chicago as the club's all-time leader in leadoff home runs (20), while ranking fifth in steals (219), seventh in doubles (249) and extra base hits (408) and eighth in runs (784).
Durham was traded to the Oakland Athletics before the 2002 baseball trading deadline for right-handed pitcher Jon Adkins. Durham's hitting helped push the A's into the 2002 playoffs. The Durham deal was a prototypical "rent a player" trade that can occur at the trading deadline. The A's, who constantly rank among the bottom teams in baseball in player salaries, made a trade for the short-term playoff push. With the A's limited finances, it was well known in baseball circles that Durham would most likely re-sign elsewhere.
After the 2002 season, Durham signed a three-year contract US$20.1 million with the San Francisco Giants with a $7 million player option for a fourth year that was later exercised. The health Durham displayed during the earlier years of his career vanished. Between 1996 and 2002, Durham appeared in at least 150 games each season, but in 2003 he only appeared in 110 games and in 2004 he appeared in 120. Recurring hamstring injuries and other injuries caused Durham to spend time on the disabled list. The injuries also hampered Durham's success when he was on the field. Durham's running game and stolen bases dropped as Durham tried to protect his hamstrings from reinjury. Despite these injuries, Durham did post solid offensive numbers during his time in the line up.
Because of Durham's injuries that limited his speed and the recurring injuries to Giants outfielder Moisés Alou, Durham was given the opportunity to bat fifth in the batting order more often. Durham was batted fifth regularly in 2006. In the 2005–2006 off-season, Durham adopted a new work out and strength conditioning routine. The result was a healthy Durham and perhaps his best offensive year in 2006 when in 137 games he batted .293 with career highs in slugging percentage (.538), home runs (26), RBIs (93).
Durham re-signed with the Giants for a two-year contract worth $14.5 million on December 2, 2006. Giants general manager Brian Sabean lauded Durham for making an impressive transition from a lead off hitter to a middle of the order run producer.
After re-signing with the Giants, Durham struggled in 2007. Durham called the season "embarrassing" and the "worst" of his career. Durham admitted that his defense had suffered because he was thinking about his hitting while on defense. Durham claimed he had trouble adjusting to the new strategy to pitch against him, which included throwing cutters inside and throwing curveballs on the outside corner. Some Giants fans and radio personalities criticized Durham's performance in 2006 as being motivated by money because 2006 was Durham's contract year. Durham denied these claims and claimed that almost every year is a contract year.
On August 21, 2007, against Sergio Mitre of the Florida Marlins, Durham fouled a pitch at the plate that bounced up and hit his groin. He would go on to single on the next pitch. "I was swinging at the first thing so I could sit down", Durham said. "Then, I end up with a knock and I had to run from first to third. It did not feel good".
On September 9, 2007, Durham hit a pinch-hit three-run homer in the eighth inning to help San Francisco beat the Los Angeles Dodgers 4–2.
On June 12, 2008, Durham got his 2000th hit off Colorado Rockies pitcher Greg Reynolds.
On July 20, 2008, Durham, was traded to the Milwaukee Brewers for minor league pitcher Steve Hammond and minor league outfielder Darren Ford.
Durham filed for free agency on November 1, 2008. He retired after rejecting a minor league deal from the Washington Nationals.