Meadows' start in showbiz was as a member of The Second City comedy troupe alongside future star Chris Farley. In 1991, Meadows landed a spot on Saturday Night Live and would go on to become a longtime cast member, appearing on the program until 2000. (This was the record for the longest tenure on the show until it was surpassed by Darrell Hammond in 2005). Meadows' lengthy tenure on the show was used as a gag in two monologues when former cast members Phil Hartman and Mike Myers returned to the show to host. Meadows' many impressions on the show included Michael Jackson, Dennis Rodman, O.J. Simpson, and Oprah Winfrey.

Among his original characters was Leon Phelps, The Ladies' Man, an eternally horny talk show host who believed himself to be the living definition of what females search for in a man. The sketch/character was adapted into a 2000 film, The Ladies Man, which followed the character's attempts to find love and a suitable outlet for his beloved radio program. Despite a surprise guest appearance on Saturday Night Live immediately following his departure to promote the movie, it was not well-received by critics or fans and subsequently flopped at the box office.

Meadows soon moved on to other projects, including a regular role on the short-lived NBC sitcom The Michael Richards Show and a supporting role in the 2004 film The Cookout. His greatest post-SNL success to date, however, was a major role as a high school principal in Mean Girls, a hit 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 rates of success. most recently, he can be seen in the 2006 film The Benchwarmers alongside his former SNL co-stars Rob Schneider and David Spade. He was also featured in the CBS show Game Show Marathon.