For one season (1984-85), he was a regular cast member on the long running NBC sketch comedy series Saturday Night Live.

Guest holds a hereditary British peerage as the 5th Baron Haden-Guest, but has publicly expressed a desire to see the House of Lords reformed as a democratically elected chamber.

Guest is married to the actress Jamie Lee Curtis, who is styled as The Right Honourable the Lady Haden-Guest; however, she opts not to use her title.

[6] In 1938, his uncle, David Guest, a lecturer and Communist Party member, was killed in the Spanish Civil War, fighting in the International Brigades.

[9] Guest began his career in theatre during the early 1970s with one of his earliest professional performances being the role of Norman in Michael Weller's Moonchildren for the play's American premiere at the Arena Stage in Washington, DC, in November 1971.

Guest also had a small but important role in it Happened One Christmas, the 1977 gender-reversed TV remake of the Frank Capra classic it's a Wonderful Life, starring Marlo Thomas as Mary Bailey (the Jimmy Stewart role), with Cloris Leachman as Mary's guardian angel and Orson Welles as the villainous Mr. Potter.

Guest played Mary's brother Harry, who returned from the Army in the final scene, speaking one of the last lines of the film: "A toast!

Along with Martin Short, Billy Crystal, and Harry Shearer, Guest was hired as a one-year-only cast member for the 1984–1985 season on NBC's Saturday Night Live.

[10] Recurring characters on SNL played by Guest include Frankie, of Willie and Frankie (coworkers who recount in detail physically painful situations in which they have found themselves, remarking laconically "I hate when that happens"); Herb Minkman, a novelty toymaker with his brother Al (played by Crystal); Rajeev Vindaloo, an eccentric foreign man in the same vein as Andy Kaufman's Latka character from Taxi; and Señor Cosa, a Spanish ventriloquist often seen on the recurring spoof of The Joe Franklin Show.

In another short film from SNL, Guest and Crystal appear in blackface as retired Negro league baseball players, "The Rooster and the King".

[11] Together, Guest, his frequent writing partner Eugene Levy, and a small band of actors have formed a loose repertory group, which appears in several films.

[12] Among the films performed in this manner, which have been written and directed by Guest, include Waiting for Guffman (1996), about a community theatre group, Best in Show (2000), about the dog show circuit, A Mighty Wind (2003), about folk singers, For Your Consideration (2006), about the hype surrounding Oscar season, and Mascots (2016), about a sports team mascot competition.

[16] In 2013, Guest was the co-writer and producer of the HBO series Family Tree, in collaboration with Jim Piddock, a lighthearted story in the style he made famous in This is Spinal Tap, in which the main character, Tom Chadwick, inherits a box of curios from his great aunt, spurring interest in his ancestry.

[20] Guest has worked multiple times with certain actors, notably with frequent writing partner Eugene Levy, who has appeared in five of his projects.