Hughes has played for the Philadelphia 76ers, Golden State Warriors, Washington Wizards, Cleveland Cavaliers, Chicago Bulls, New York Knicks, Sacramento Kings, Charlotte Bobcats, and Orlando Magic.

During his 76ers tenure, he and fellow guard Allen Iverson were nicknamed "the Flight Brothers", for their above-the-rim play style.

[2] Hughes participated in the 2000 Slam Dunk Contest in Oracle Arena (home of the Golden State Warriors) in Oakland, California.

His last performance before the injury came in a 97–84 home upset of the Detroit Pistons, in which he scored 16 points on 7–10 shooting to go with two steals, five rebounds and three assists.

On May 2, 2006, Hughes was recipient of the inaugural Austin Carr Good Guy Award, designed to recognize the Cavaliers player who is cooperative and understanding of the media, the community and the public.

[7] On February 18, 2010, Hughes was traded to the Sacramento Kings in a three team deal that also moved Tracy McGrady to the Knicks.

[15] In November 2020, Hughes announced plans to open two cannabis dispensaries in St. Louis with former Knicks teammate Al Harrington.