A free agent in 2002, Lofton signed a one-year, $1.025 million contract with the Chicago White Sox. "I looked at the different opportunities that I had and this was a team that won 83 games last year while they were banged up. Cleveland lost four good players from last year's team, and that's going to be hard to replace. This was an easy decision", Lofton said on signing with the White Sox. White Sox general manager Kenny Williams had stated when Lofton was healthy, like he was during the second half of the 2001 season, Chicago had obtained one of the best leadoff hitters in the game. When the White Sox were paired against the Indians in April during a three-game series at Chicago, the Indians were on a 10-game winning streak and at 11–1, had the best record in the majors. The White Sox ended the streak and for the series, Lofton was 6-for-14 with six runs scored. "You can't say enough about him, his effort, his intensity. He's been simply amazing", said White Sox manager Jerry Manuel. Lofton appeared in 93 games with the White Sox and hit .259 with 42 RBIs and 22 stolen bases. On July 28, he was traded to the San Francisco Giants of the NL for minor leaguers Ryan Meaux and Félix Díaz.
In the Giants' match-up with the St. Louis Cardinals in the 2002 NLCS, Lofton delivered a key hit to help the Giants win their first pennant since 1989. In the ninth inning, Cardinals manager Tony La Russa summoned left-handed reliever Steve Kline to face Lofton, who had already notched two singles in the game. Giants manager Dusty Baker considered bringing a right-handed hitter to pinch-hit for Lofton, but decided against doing so on the advice of his 3-year-old son. Lofton hit a first-pitch single to the outfield, scoring David Bell from second base and creating a 2–1 Giants victory. After the game, Baker remarked, "I just knew Kenny was focused and I know you can't keep Kenny down for too long. That's why we got Kenny over here. He's a big-game player and he's been great in the playoffs." The Giants held a five-run lead in the seventh inning of game six of the World Series against the Anaheim Angels, but eight outs away from winning the World Series, the Angels rallied to win 6–5. The Angels took game seven the following night, with Lofton flying out to Darin Erstad in center to end that game and the World Series, and for the second time in his career, Lofton had lost a World Series.
From 2002 to 2007, Lofton played for eight teams and made it to the postseason with four of them. Joe Torre said, after Lofton had been to the playoffs in 11 of the past 13 seasons and played for 11 clubs in his career, "He bounced around a lot of clubs for a reason: They felt he could help them. He did a hell of a job." As Rollie Fingers wrote, "On one hand, Lofton could be seen as a catalyst who magically sparked his teams into playoff contention, but others could say that it was simply a case of top playoff contenders repeatedly seeing him as the final piece of their puzzle."