Cheadle's career started with supporting roles in Hamburger Hill (1987), Colors (1988), Devil in a Blue Dress (1995), Rosewood (1997), Boogie Nights (1997), and Bulworth (1998).

Cheadle was nominated for an Academy Award for Best Actor for his portrayal of Paul Rusesabagina in the historical drama film Hotel Rwanda (2004).

Cheadle joined the Marvel Cinematic Universe portraying James "Rhodey" Rhodes / War Machine, beginning with Iron Man 2 (2010).

On television, Cheadle earned nominations for Primetime Emmy Award for Outstanding Lead Actor in a Comedy Series for his roles as Marty Kaan in House of Lies (2012–2016) and Maurice Monroe in Black Monday (2019–2021).

[6] During his time at CalArts, Cheadle along with his friends acted in numerous plays such as Athol Fugard's "Master Harold"...and the Boys, The Island; and My Name Could Be Anne in the black box theater.

[7] Cheadle became eligible for his Screen Actors Guild card when he appeared as a burger joint employee in the 1985 comedy Moving Violations.

[9] In 1989, he appeared in a music video for Angela Winbush's number-two hit single "It's the Real Thing" as a car wash employee performing dance moves.

[16] Cheadle's portrayal of Sammy Davis Jr. in the 1998 TV movie The Rat Pack won him a Golden Globe Award and an Emmy nomination.

[17] A year later he starred as Grant Wiggins, a school teacher in the film A Lesson Before Dying, which won the Primetime Emmy Award for Outstanding Television Movie.

The following year, he played Basher Tarr in the heist film Ocean's Eleven, a remake of the 1960 Rat Pack original.

Cheadle made a guest appearance in the ninth season of the television series ER, playing the role of Paul Nathan, a medical student who suffers from Parkinson's disease.

Abe Sutton (along with Etan Bednarsh), one of the finalists in this NFL contest, played on this commercial by proposing an ad in which every player on a football team is Don Cheadle.

[22] In March 2007, Cheadle starred with comedian Adam Sandler in Mike Binder's Reign Over Me, a comedy-drama about a man who has slipped away from reality after the death of his wife and three daughters on 9/11.

[28] In 2010, Cheadle assumed the role of James "Rhodey" Rhodes / War Machine in Iron Man 2 (2010), replacing Terrence Howard.

[39] In 2021, Cheadle starred in the period crime thriller No Sudden Move, in which he played Curt Goynes, a gangster in 1950s Detroit.

[42][43] In February 2024, it was announced that Cheadle had joined the main cast for Peacock's crime drama miniseries Fight Night: The Million Dollar Heist.

Cheadle and John Prendergast co-authored a book about this issue entitled Not on Our Watch: The Mission to End Genocide in Darfur and Beyond.

With George Clooney, Brad Pitt, Matt Damon, David Pressman, and Jerry Weintraub, Cheadle co-founded the Not on Our Watch Project, an organization focusing global attention and resources to stop and prevent mass atrocities.

[54] He and Harrison Ford created a documentary event series entitled Years of Living Dangerously that provided first-hand reports on those affected by, and seeking solutions to climate change.