Kimmel was born in the New York City borough of Brooklyn, and is of Italian and German descent. The family moved to Las Vegas, Nevada, when he was nine years old. He graduated from Ed W. Clark High School, and then attended University of Nevada, Las Vegas for one year before attending Arizona State University for two years without completing a degree. Kimmel and his former wife, Gina, married in June 1988. They have a son, Kevin, and a daughter, Katie. The marriage ended in separation in early 2002. Kimmel then dated comedian Sarah Silverman for five years, ending in the summer of 2008 and then reuniting as of October 2008. The couple split again in March 2009.

Kimmel is an avid music fan, and plays the bass clarinet. He got a chance to showcase his talent during a July 20, 2008, concert in Costa Mesa, California, featuring the Mighty Mighty Bosstones, when he took the stage and played bass clarinet on their hit song "The Impression That I Get."

Kimmel has narcolepsy.

Kimmel will serve as host of Los Angeles' sixth annual feast of San Gennaro from September 28-30. 2009.

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. Ten months later, Kimmel and Voss were fired by KZOK (reason unk.) and were fired again (another mystery) a year later at WRBQ-FM in Tampa, Florida. Kimmel went from Tampa to host his own show at KCMJ-FM in Palm Springs, California (where Kimmel convinced a young Carson Daly to drop out of college and become his intern because college interns were unknown then.) From Palm Springs, Kimmel landed a job with Mike Elliott at 93.7 KRQ in Tucson. Kimmel and Elliott were fired after one year (mysterious again). From KRQ, Kimmel was hired as sports guy/comedy writer for the Kevin and Bean morning show at KROQ-FM (former employer of Carson Daly) , Los Angeles, where he was known as "Jimmy the Sports Guy." Kimmel spent five years at KROQ, leaving in 1999 to focus on television.

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 loutish 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.

In 1999, during his time with Win Ben Stein's Money, Kimmel was also co-host (with Adam Carolla) and co-creator (with Daniel Kellison) of Comedy Central's The Man Show. Kimmel permanently left Win Ben Stein's Money in 2001. He was replaced by comedian Nancy Pimental who was eventually replaced by Kimmel's cousin Sal Iacono. Kimmel, Carolla, and Kellison's success with The Man Show allowed them to create and produce other TV shows under the banner Jackhole Industries, including Crank Yankers for Comedy Central (on which Kimmel plays the characters, "Elmer Higgins," "Terrence Catheter," "The Nudge," "Karl Malone" and himself) and later The Andy Milonakis Show for MTV2. Kimmel also produced and co-wrote the feature film Windy City Heat, which won the Comedia Award for Best Film at the Montreal Comedy Festival.

In January 2003, Kimmel permanently left The Man Show to host his own late-night talk show, Jimmy Kimmel Live! on ABC. In the April 2007 issue of Stuffmagazine.com, Kimmel was named the "biggest badass on TV". Kimmel said it was an honor but clearly a mistake.

Kimmel usually ends his show with, "My apologies to Matt Damon, we ran out of time." However, on one of his shows, he "interviewed" Matt Damon, only to say just a few seconds later, "Sorry, but once again we are completely out of time." Matt appeared to become angry, but people questioned whether this was real or a joke. Kimmel confirmed that this was in fact a joke. Jimmy Kimmel Live is also broadcast on Irish digital tv channel 3e.

In February 2008 Kimmel showed a mock music video with a panoply of stars called, "I'm Fucking Ben Affleck," as "revenge" after his then-girlfriend Sarah Silverman and Matt Damon recorded a similar video, "I'm Fucking Matt Damon". Silverman's video originally aired on Jimmy Kimmel Live!, and became an "instant YouTube sensation." Kimmel's "revenge" video featured himself, Ben Affleck, and a big lineup of stars, particularly in scenes spoofing the 1985 "We Are the World" video: Brad Pitt, Don Cheadle, Cameron Diaz, Robin Williams, Harrison Ford, Dominic Monaghan, Benji Madden and Joel Madden from Good Charlotte, Lance Bass, Macy Gray, Dicky Barrett of the Mighty Mighty Bosstones, Josh Groban, Huey Lewis, Perry Farrell, Christopher Mintz-Plasse, Pete Wentz, Meat Loaf, Rebecca Romijn, Christina Applegate, Dom Joly, Mike Shinoda, Lauren Conrad and Joan Jett.

As a tradition, celebrities voted off Dancing with the Stars appear on Jimmy Kimmel Live!, causing Kimmel to describe himself as "the three-headed dog the stars must pass on their way to No-Dancing Hell." In the 2008 season of his show, Kimmel started another tradition of ceremonially burning the dancers' shoes after they were voted off DWTS.