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. 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.