Kimmel began working in the radio industry while in high school, hosting a Sunday night interview show on UNLV's college station KUNV.

While attending Arizona State University, he became a popular caller to the KZZP-FM afternoon show hosted by radio personalities Mike Elliott and Kent Voss in Phoenix, Arizona. In 1989, Kimmel landed his first paying job alongside Voss as morning drive co-host of The Me and Him Show at KZOK-FM in Seattle, Washington.

Kimmel's television career began as the comedic counterpart to Ben Stein on the game show Win Ben Stein's Money which began airing on Comedy Central in 1997. His quick wit and everyman personality was a counterpoint to Ben Stein's monotone performing style and patrician demeanor. This combination earned the pair an Emmy award for Best Game Show Host.

On Monday, October 15, 2007, Kimmel was banned from ESPN's Monday Night Football.

Kimmel's other television work included being the on-air football prognosticator for FOX NFL Sunday for four years. He has had numerous appearances on other talk shows including, but not limited to, Live with Regis and Kelly, The Howard Stern Show, The Ellen DeGeneres Show, and Late Show with David Letterman Kimmel is a fan of David Letterman, who, together with Howard Stern, were his idols growing up.

He has appeared on The Late Show seven times between 1997 and 2002. Kimmel is a three-time host of the American Music Awards and served as roast master for the New York Friars' Club Roast of Hugh Hefner and Comedy Central Roasts of Pamela Anderson.