Duke was born in Poughkeepsie, New York, the son of Ethel Louise (née Douglas) and William Henry Duke Sr. He attended Franklin D. Roosevelt High School in Hyde Park and later received his first instruction in the performing arts and in creative writing at Dutchess Community College in Poughkeepsie. 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.
Standing an imposing 6 ft 4½ 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) where he played a gay pimp.
As the action-film-oriented genre became more popular, Duke's presence was perfect to portray a string of "tough guy" roles. He notably worked opposite Arnold Schwarzenegger in both Commando and Predator, followed by a role as a police chief in the 1988 Carl Weathers vehicle Action Jackson. Duke appeared uncredited as a DEA officer in The Limey (1999), as well as a police chief opposite Steven Seagal in Exit Wounds. He played a detective investigating a murder in Menace II Society, in which he delievered the often-quoted line, "You done fucked up, you know that, don't you?". He played a corrupt law enforcement agent in two films opposite Mel Gibson - Bird on a Wire (as an FBI agent) and Payback (as a police detective). Duke appears in X-Men: The Last Stand as Trask, Washington in National Security, Levar in Get Rich or Die Tryin' and Nokes in Bad Country.
Duke directed the TV movie The Killing Floor in 1985. He began directing theatrical 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). In 2007 he directed the reenactments in the award-winning, PBS-broadcast documentary Prince Among Slaves produced by Unity Productions Foundation. 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 teamed with screenwriter Bayard Johnson to co-produce Cover, a 2007 film which explores the HIV epidemic.
Duke made an early appearance on Kojak as 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 had a starring role in the short-lived TV series Palmerstown, USA, produced by Norman Lear and Roots author, Alex Hailey. Although the series was critically acclaimed and won an Emmy, it ran for only 17 episodes in the 1980-81 television season.
Duke was cast as recurring character Capt. Parish in the action television series/crime drama Fastlane. He made a guest appearance on Baisden After Dark in the episode broadcast on July 18, 2008 and guest-starred on Cold Case as Grover Boone, a corrupt politician, in the 2008 episode "Street Money".
Duke voiced a detective in the episode "Thank You for Not Snitching" of the animated television series The Boondocks. The character and his entire scene were references to Menace II Society.
Duke also appears in Busta Rhymes' music video "Dangerous".
Duke also appears in an episode of Law and Order SVU as a lawyer.