[1] He is best known for his portrayal of astronaut David Bowman in the 1968 film 2001: A Space Odyssey and its 1984 sequel, 2010: The Year We Make Contact.

[3][7] Dullea made his debut in a television adaptation of Mrs. Miniver (1960) with Maureen O'Hara, playing the German pilot.

[8] He was in demand for guest appearances on television shows such as Route 66, The New Breed, Checkmate and Cain's Hundred.

Dullea made his film debut in 1961 in Hoodlum Priest, cast on the strength of his work on Route 66.

Metro-Goldwyn-Mayer and Disney offered long-term contracts (roles in Two Weeks in Another Town and Bon Voyage) but Dullea turned both down.

[7] In 1965, he guest-starred as Lieutenant Kurt Muller in the episode titled "To Heinie, with Love" of Twelve O'Clock High.

Dullea played the son of Lana Turner's character in Ross Hunter's remake of Madame X (1966), which underperformed commercially.

[16] His first Broadway appearance was in 1967 in Ira Levin's Dr. Cook's Garden with Burl Ives, which only had a short run.In 1968, Dullea appeared as astronaut David Bowman in Stanley Kubrick's film 2001: A Space Odyssey, which became a box-office success and is recognized by critics, filmmakers and audiences as one of the greatest and most influential films ever made.

He had success on Broadway, starring in the 1969 hit comedy Butterflies Are Free with Eileen Heckart and Blythe Danner.

Dullea was in Paul and Michelle (1974) and had a major role in the Canadian production, 1974 cult classic Black Christmas as Peter Smythe, Jess Bradford’s boyfriend.

Also in 1974, he played Brick in the Tennessee Williams classic Cat on a Hot Tin Roof opposite Elizabeth Ashley and Fred Gwynne on Broadway which ran 160 performances.

He appeared in Law and Order (1976) for TV, the Canadian film Welcome to Blood City (1977), The Haunting of Julia (1977), and Three Dangerous Ladies (1977), the British Leopard in the Snow (1977), the Australian Because He's My Friend (1978), and some films for TV: The Legend of the Golden Gun (1978), an adaptation of Brave New World (1980), The Hostage Tower (1980), No Place to Hide (1981), and BrainWaves (1982).

[3] Dullea appeared as a regular cast member in the Canadian soap opera Loving Friends and Perfect Couples, which ran in 1983.

In December 2004, for their annual birthday celebration to "The Master", the Noël Coward Society invited Dullea as the guest celebrity to lay flowers in front of Coward's statue at New York's Gershwin Theatre, thereby commemorating the 105th birthday of Sir Noël.

In 2006, he played Andrew Keener in Cost of Capital, which was the 16th episode, of the 16 season of the original Law & Order American television series, and he had a role as a US Senator and a "major influence and mentor" to Matt Damon's character, in Robert De Niro's film The Good Shepherd (2006).

In October 2012, Dullea performed the role of Heinrich Mann in the Guthrie Theater production of Tales from Hollywood by Christopher Hampton.

He was in Isn't It Delicious (2013) with his wife Mia Dillon, Infinitely Polar Bear (2014), Space Station 76 (2014), and April Flowers (2017).

[30] During August and September 2013, Keir Dullea starred as Big Daddy in Cat on a Hot Tin Roof, playing opposite wife Mia Dillon in a joint production for Wellfleet Harbor Actors Theater and Provincetown Tennessee Williams Theater Festival.

Between July 10-August 2, 2015, Dullea and wife Mia Dillon were joined by Todd Cerveris, Cameron Clifford, Don Noble and Christa Scott-Reed in the Bucks County Playhouse production of Ernest Thompson's On Golden Pond.

Dullea was cast as Fleet Admiral Terrence Hood, a high-ranking UNSC officer, in the Paramount+ TV series Halo which premiered on March 24, 2022 (2022-03-24).