He has starred in such films as The Thing (1982), Platoon (1986), Road House (1989), Men at Work (1990), Final Analysis (1992), The Quick and the Dead (1995), Larger than Life (1996), Armageddon (1998), Where the Heart Is (2000), Novocaine (2001), Head of State (2003), Mr. & Mrs. Smith (2005), Gamer (2009), and American Fiction (2023).

His Emmy-winning voice-over career includes work as the narrator of Ken Burns films such as Jazz (2001), The War (2007), and Muhammad Ali (2021).

On television, he portrayed Goliath in Gargoyles (1994–1997), Al Simmons / Spawn in Todd McFarlane's Spawn (1997–1999), The Flame King in Adventure Time (2012–2017), Andre Curtis / The President in Rick and Morty (2015–present), King Andrias in Amphibia (2020–2022), Dr. Tenma in Pluto (2023), Husk in Hazbin Hotel (2024–present), and Mephisto in Hit-Monkey (2024–present).

Video game roles include the Arbiter Thel 'Vadamee in the Halo franchise (2004–2015), Julius Little and himself in the Saints Row series (2006–2017), Admiral Anderson in the Mass Effect series (2007–2013), Chaos in Dissidia Final Fantasy (2008), Sergeant Foley in Call of Duty: Modern Warfare 2 (2009), Grimlock in Transformers: EarthSpark and Commander Zavala in Destiny 2: The Final Shape.

His mother, Dolores (née Dickenson), was a manager at New York Telephone, and his father, Lester Williams, worked as a director of payroll operations.

[6] In 1980–81, David toured the country with John Houseman's The Acting Company in productions of A Midsummer Night's Dream and Samuel Beckett's Waiting for Godot.

Less than two years later, he went on to star as Childs, opposite Kurt Russell in John Carpenter's The Thing, starting his lengthy on-screen career.

Roles in other films followed, in Volcano,There's Something About Mary, Requiem for a Dream, Pitch Black, Barbershop, Agent Cody Banks, Head of State, Hollywood Homicide, Agent Cody Banks 2: Destination London, The Chronicles of Riddick, Crash, ATL, Delta Farce and First Sunday.

At the same time, he has appeared in numerous independent films including the critically acclaimed Requiem for a Dream, playing the role of Big Tim.

[3] In 2015, David was cast in the leading role alongside Lynn Whitfield in the Oprah Winfrey Network drama series Greenleaf.

David provided the voice of police detective Alex Cross for the audiobook versions of three novels by James Patterson: Cat and Mouse (1997), Pop Goes the Weasel (1999), and Roses are Red (2000).

He voiced Apollo the Sun God in Hercules, Council Member in Final Fantasy: The Spirits Within, the Black Cat in Coraline, Sergeant Foley in Call of Duty: Modern Warfare 2, Dr. Facilier in The Princess and the Frog, and Big Man in The Spectacular Spider-Man episode "Survival of the Fittest".

[16] Keith David also has a recurring role as the President of the United States in the adult animated series Rick and Morty.

[17] In 1992, David received a Tony Award nomination for Best Supporting Actor in a Musical for his performance in Jelly's Last Jam.

[18] In 1995, David acted alongside Whitney Houston, Cedric the Entertainer, and Samuel E. Wright in the 1995 Apollo revival of The Wiz.

David appeared in the 2013 revival of August Wilson's Joe Turner's Come and Gone at the Mark Taper Theater in Los Angeles.

[26] In April 2023, David endorsed author and Democratic primary challenger Marianne Williamson for president in the 2024 elections.