Following a period of stand-up comedy performances and humorous song recordings, his first famous role was as Garth Gimble and Barth Gimble in the television nighttime absurdist soap opera Mary Hartman, Mary Hartman (1976), which led to spin-off comedy talk shows Fernwood 2-Night (1977) and America 2-Night (1978), in which he played the emcee Barth Gimble, opposite Fred Willard as sidekick Jerry Hubbard. During 1984 he starred in a CBS sitcom, Domestic Life, with Megan Follows playing his teenaged daughter. He also has appeared as a guest on the game show Hollywood Squares, appearing as the center square in the show's final season.

He has also acted in feature films, including:

FM (1978) Serial (1980) My Bodyguard (1980) Take This Job and Shove It (1981) Mr. Mom (1983) Growing Pains (1984) Clue (1985) as Colonel Mustard Mrs. Doubtfire (1993) Jingle All the Way (1996) Recurring roles followed on several television series:

Roseanne (as Leon, Roseanne's homosexual boss; Fred Willard played his partner) Family Dog Sabrina, the Teenage Witch (as Willard Kraft, Sabrina's high-school principal) The Ellen Show During the 1980s, Mull starred in a series of television commercials for Michelob, and in a series of television and radio commercials for Red Roof Inn (a chain of budget-oriented hotels owned by Accor) during the mid-1990s.

Mull has recently done the voice of Vlad Masters/Vlad Plasmius on Danny Phantom.

In late 2004, he portrayed "Gene Parmesan," a private investigator who was better at showing up in strange places in strange disguises than actually finding anything out, on the FOX TV series Arrested Development. The episode was called "Amigos."