ABC created Jimmy Kimmel Live! as a follow-up to Nightline after the cancellation of Politically Incorrect in 2002; Kimmel had previously co-hosted the Comedy Central sketch show The Man Show before being announced as host in November 2002.

Despite its 'Live!' title, the show has not regularly aired live since April 23, 2004, after actor Thomas Jane unleashed a barrage of swearing during a taping that censors could not properly bleep, leading the show to switch to taped broadcasts.

Sidekick Guillermo Rodriguez was originally a parking lot security guard who became part of the show after being caught sleeping in announcer Dicky Barrett's car.

Kimmel's real-life uncle, Francis 'Uncle Frank' Potenza, a former NYPD officer and Frank Sinatra bodyguard, served as the show's security guard and recurring on-camera personality until his death in 2011.

Starting in 2005, Kimmel began ending episodes by apologizing to actor Matt Damon for 'running out of time,' a running joke that began spontaneously during a low-quality episode and was continued at the producer's suggestion; it grew into a years-long satirical feud involving elaborate sketches and even a 2013 anniversary episode titled 'Jimmy Kimmel Sucks!' where Damon took over hosting duties.

In a 2008 segment, Kimmel's then-girlfriend Sarah Silverman revealed via music video that she was 'fucking Matt Damon,' prompting Kimmel to release his own star-studded retaliatory video targeting Ben Affleck, featuring cameos from Brad Pitt, Robin Williams, Harrison Ford and many others; the segment won a Creative Arts Emmy for Outstanding Original Music and Lyrics.

During the 2010 Tonight Show conflict between Jay Leno and Conan O'Brien, Kimmel wore a gray wig and fake chin to perform an entire episode in character as Leno, mocking the situation, which led to a tense on-air confrontation when Kimmel later appeared as a guest on Leno's actual show.

During the COVID-19 pandemic, the show suspended production, then resumed taping from Kimmel's own house starting March 30, 2020, with 30-minute episodes, before eventually returning to the Hollywood Masonic Temple studio without a live audience in September 2020.

In September 2025, FCC chair Brendan Carr publicly threatened action against ABC over Kimmel's monologue comments regarding the killer of Charlie Kirk, prompting Nexstar and Sinclair to pull the show from their affiliates and ABC to suspend it indefinitely; the suspension sparked boycotts, protests by the Writers Guild of America, and a Change.org petition with over 60,000 signatures before Kimmel returned to air five days later.

In 2019, ABC and the show were fined $395,000 by the FCC for misusing the Emergency Alert System tone during an October 2018 episode.