In Fall 1990, Saturday Night Live producer Lorne Michaels saw Meadows perform at Second City, and brought him into a meeting in New York, without auditioning for the show, where he read a line for a sketch with Steve Martin, Paul Simon, and Ralph Nader, which was for the first Five-Timers Club sketch for the Tom Hanks episode on December 8, 1990, in which Meadows did not appear at all.

Some skits had Meadows playing a fictionalized version of himself, such as being a fan of ice hockey on Weekend Update, stating his dissatisfaction with the 1994 NHL lockout and remarking, "What am I supposed to do about this; watch basketball?"

He played a high-school principal in Mean Girls, a film written by (and co-starring) fellow SNL cast member Tina Fey.

Meadows has appeared in other feature films, including Coneheads, It's Pat, and Wayne's World 2, all of which were based on popular SNL characters and had varying degrees of success.

Winsome, a conservative pundit and entrepreneur (who made an appearance at the Rally to Restore Sanity and/or Fear), and starred in The Bill Engvall Show and Curb Your Enthusiasm.

On May 31, 2008, Meadows threw out a ceremonial first pitch and conducted the seventh-inning stretch at Wrigley Field during a Chicago Cubs game against the Colorado Rockies.

Meadows continues to perform improv in Chicago and Los Angeles, most frequently at venues such as the ImprovOlympic and Upright Citizens Brigade Theatre.

On February 17, 2023, Meadows was announced to reprise his role as Principal Ron Duvall from the first Mean Girls film in the stage-to-screen adaptation of the Broadway musical.