Duke was born in Poughkeepsie, New York, the son of Ethel Louise (née Douglas) and William Henry Duke Sr. He received his first instruction in the performing arts and in creative writing at Dutchess Community College in Poughkeepsie under Professor Constance Kuhn in drama and Professor Howard Winn in creative writing. His first major acting role at Dutchess was as the lead in Eugene O'Neill's Emperor Jones. After graduation from Dutchess he went on to Boston University for further instruction in drama and for his B.A. After studying at New York University's Tisch School of Arts and the AFI Conservatory, he appeared on Broadway in the 1971 Melvin Van Peebles musical Ain't Supposed to Die a Natural Death. He directed episodes of several noteworthy 1980s television series, including Hill Street Blues and Miami Vice. Known to family and close friends as Maccy Bub after a cat he owned in his youth named Macintosh and the waterproof jacket he often wore.

Standing an imposing 6 ft 4 1/2 in and featuring a closely shaved head, Duke first became a familiar face to moviegoers in Car Wash (1976) where he portrayed fierce young Black Muslim revolutionary Abdullah Mohammed Akbar (formerly known as Duane), and expanded his repertoire with American Gigolo (1980).

As the action-film-oriented genre became more popular, Duke's presence was perfect to portray a myriad of 'tough guy' roles, chiefly alongside Arnold Schwarzenegger in Commando and Predator, as well as the police chief in Carl Weathers' movie Action Jackson. He played a detective investigating a murder in Menace II Society with his now classic line "You know you done fucked up now... you know that, don't you?" He was a dirty cop in the Mel Gibson revenge movie Payback and has appeared in X-Men: The Last Stand as Bolivar Trask. He also played the role of Levar in the 2005 film Get Rich or Die Tryin'.

Duke began directing feature-length films in the 1990s with crime dramas A Rage in Harlem (1991), Deep Cover (1992) and Hoodlum (1997). He also directed The Cemetery Club (1993) and Sister Act 2: Back in the Habit (1993), starring Whoopi Goldberg. For television, Duke directed the A&E Network original film, The Golden Spiders: A Nero Wolfe Mystery (2000).

Duke continues to act and direct for both the small and silver screens. He is also a mentor for young African Americans aspiring to work in the performance arts.

Duke made an early appearance on Kojak as the character, Sylk in the Episode, "Bad Dude" in the third season of the series. He guest starred in the fourth episode of Lost in its third season as Warden Harris, in the episode "Every Man for Himself". He also guest starred in Battlestar Galactica in the season two episode "Black Market".

Duke was also cast as recurring character Capt. Parish in the action television series/crime drama Fastlane (September 18, 2002 – April 25, 2003).

Duke also made a guest appearance on Baisden After Dark July 18, 2008.

Duke also guest starred on Cold Case as Grover Boone, a corrupt politician, in the 2008 episode "Street Money".

Duke did a voice over as himself playing a detective in the episode "Thank You for Not Snitching" of the television series The Boondocks.