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 D.C. in November 1971. Guest continued with the production when it moved to Broadway in 1972. The following year he began making contributions to The National Lampoon Radio Hour for a variety of National Lampoon audio recordings. He both performed comic characters (Flash Bazbo—Space Explorer, Mr. Rogers, music critic Roger de Swans, and sleazy record company rep Ron Fields) and wrote, arranged and performed numerous musical parodies (of Bob Dylan, James Taylor and others). He was featured alongside Chevy Chase and John Belushi in the Off-Broadway revue National Lampoon's Lemmings. Two of his earliest film roles were small parts as uniformed police officers in the 1972 film The Hot Rock and 1974's Death Wish.

Guest studied acting at New York University's Graduate Acting Program at the Tisch School of the Arts, graduating in 1971.

Guest played a small role in the 1977 All In the Family episode "Mike and Gloria Meet", where in a flashback sequence Mike and Gloria recall their first blind date, set up by Michael's college buddy Jim (Guest), who dated Gloria's girlfriend Debbie (Priscilla Lopez).

Guest married Actress Jamie Lee Curtis in 1984 at the home of their mutual friend, Rob Reiner. They have two adopted children: Anne (born 1986) and Thomas (born 1996). Because Guest's children are adopted, they cannot inherit the family barony under the terms of the letters patent that created it, though a 2004 Royal Warrant addressing the style of a peer's adopted children states that they can use courtesy titles. The current heir presumptive to the barony is Guest's younger brother, actor Nicholas Guest.

He appeared as Count Rugen in The Princess Bride. He had a cameo role as the first customer, a pedestrian, in the 1986 musical remake of The Little Shop of Horrors, that also featured Steve Martin. As a co-writer and Director, Guest made the Hollywood satire The Big Picture.

Upon his father succeeding to the family peerage in 1987, he was known as The Hon. Christopher Haden-Guest. This was his official style and name until he inherited the barony in 1996.

Guest appeared as Dr. Stone in A Few Good Men (1992), as Lord Cromer in Mrs Henderson Presents (2005) and in the 2009 comedy The Invention of Lying.

Guest became the 5th Baron Haden-Guest, of Great Saling, in the County of Essex, when his father died in 1996. He succeeded upon the ineligibility of his older half-brother, Anthony Haden-Guest, who was born prior to the marriage of his parents. According to an article in The Guardian, Guest attended the House of Lords regularly until the House of Lords Act 1999 barred most hereditary peers from their seats. In the article Guest remarked:

Guest holds a hereditary British peerage as the 5th Baron Haden-Guest, and has publicly expressed a Desire to see the House of Lords reformed as a democratically elected chamber. Though he was initially active in the Lords, his career there was cut short by the House of Lords Act 1999, which removed the right of most hereditary peers to a seat in the parliament. When using his title, he is normally styled as Lord Haden-Guest. Guest is married to the Actress and author Jamie Lee Curtis.

He is also currently a member of the musical group The Beyman Bros, which he formed with childhood friend David Nichtern and Spinal Tap's current keyboardist C. J. Vanston. Their debut album Memories of Summer as a Child was released on January 20, 2009.

In 2010, the United States Census Bureau paid $2.5 million to have a television commercial directed by Guest shown during television coverage of Super Bowl XLIV.

On August 11, 2015, Netflix announced that Mascots, a film about the competition for the World Mascot Association championships's Gold Fluffy Award, would debut in 2016.