D.L. Hughley grew up in South Central Los Angeles and had a difficult upbringing, getting kicked out of high school and becoming a member of the Bloods gang. After his cousin was shot, Hughley turned his life around, got a GED and a job and, after prompting by his wife, LaDonna, tried his hand at stand-up comedy. His comedy was a huge success and in 1992 he was picked to be the first host of BET's Comicview. He also appeared in the 3rd season of The Fresh Prince Of Bel-Air as an old friend of Will Smith trying out for an audition as a comedian.

By 1997, Hughley went on a nationwide stand-up comedy tour with Steve Harvey, Cedric the Entertainer, and Bernie Mac as the Kings of Comedy. The comedy act was later put into a film by Spike Lee called The Original Kings of Comedy.

In 1998, Hughley was given his own TV sitcom, The Hughleys, on ABC. It received high ratings in its first season, thanks in part to a lead-in by the popular Home Improvement. However, by the following season, the show was moved to the low-rating TGIF segment on Friday nights and the ratings tanked. In 2000, ABC cancelled the show, but it was granted a reprieve by UPN, which ran it for an additional two seasons before cancelling it again.

During this time Hughley began working on an acting career, providing the voice of the Gadgetmobile in the 1999 film Inspector Gadget and performing in Scary Movie 3. He also stuck with his stand-up comedy roots, becoming host of Comedy Central's Premium Blend in 2003. In 2005, his late-night talk show Weekends at the D.L. premiered on Comedy Central.

He is number 54 on Comedy Central's list of the 100 Greatest Stand-ups of All Time.