Billy Crystal gained prominence in the 1970s for playing Jodie Dallas on the ABC sitcom Soap and became a Hollywood film star during the late 1980s and 1990s, appearing in the critical and box office successes When Harry Met Sally... (1989), City Slickers (1991), and Analyze This (1999) and providing the voice of Mike Wazowski in Disney/Pixar's Monsters, Inc. franchise.

Crystal's earliest prominent role as Jodie Dallas on Soap, was one of the first unambiguously homosexual characters in the cast of an American television series. He continued in the role during the series' entire 1977–1981 run.

In 1982, Crystal hosted his own variety show, The Billy Crystal Comedy Hour on NBC. When Crystal arrived to shoot the fifth episode, he learned it had been canceled after only the first two aired.

After hosting Saturday Night Live twice on March 17, 1984 and the show's ninth season finale on May 5, he joined the regular cast for the 1984-85 season. His most famous recurring sketch was his parody of Fernando Lamas, a smarmy talk-show host whose catchphrase, "You look... mahvelous!," became a media sensation.

Crystal subsequently released an album of his stand-up material titled Mahvelous! in 1985, as well as the single "You Look Marvelous", which peaked at No. 58 on the Billboard Hot 100 in the US, and No. 17 in Canada.

Also in the 1980s, Crystal starred in an episode of Shelley Duvall's Faerie Tale Theatre as the smartest of the three little pigs.

In 1996, Crystal was the guest star of the third episode of Muppets Tonight! and hosted three Grammy Awards Telecasts: the 29th Grammys; the 30th Grammys; and the 31st Grammys.

He has hosted the Academy Awards nine times, beginning in 1990 and most recently in 2012; a record second only to that of Bob Hope, who hosted 14 times.

Crystal currently co-stars alongside Josh Gad on the FX comedy series The Comedians, which premiered on April 9, 2015.