While Lennon was a member of The New Group, the comedy troupe changed its name to The State. As they performed material at theaters and clubs in New York City, they worked on the MTV show You Wrote It, You Watch It. This led to their self-titled series The State, which ran from 1993 to 1995 on MTV. It was nominated for a 1995 Cable Ace Award for Best Comedy Series. In the same year, they created The State's 43rd Annual All-Star Halloween Special for CBS.
After the departure of The State from MTV and failed long-term deals with both ABC and CBS, Lennon, along with Kenney, Robert Ben Garant, and Michael Ian Black, created and starred in the Comedy Central program Viva Variety (1997–99). The show was based on "The Mr. and Former Mrs. Laupin Variety Programme," a sketch which Lennon had written for the final season of The State. Viva Variety received a 1997 Cable Ace Award nomination for Best Comedy Series.
After Viva Variety, Lennon, Kenney, and Garant created and starred in Reno 911! (2003–2009). The series was initially slated to be on Fox, but the channel rejected it for being too risqué and the program ended up on Comedy Central.
Lennon has appeared as a guest star in dozens of TV shows including The League, Childrens Hospital, Party Down, New Girl, How I Met Your Mother, Comedy Bang! Bang!, and Don't Trust the B— in Apartment 23. One of his notable guest starring roles was as Joey Tribbiani's blackjack-dealing "identical hand twin" on the Friends fifth-season finale ("The One In Vegas", Pts. I and II). Additionally, he has appeared on Jimmy Kimmel Live!, The Tonight Show, The Daily Show, Late Night with Jimmy Fallon and with 31, had the second-highest number of appearances on The Late Late Show with Craig Ferguson. In 2008, he began doing stand-up comedy, occasionally playing guitar, and incorporating music. He appeared on The Meltdown with Jonah and Kumail, John Oliver's New York Stand-Up Show, The Jeselnik Offensive, and The Benson Interruption. He was the guest on the first episode of Chris Hardwick's The Nerdist Podcast, which was recorded in Lennon's garage. In 2010, Lennon and Garant created and starred in a sitcom pilot, The Strip, for NBC. In May of that year, NBC announced that it would not produce it as a series.
In November and December 2011, Lennon filled in as guest voice for the robot sidekick Geoff Peterson on the CBS show The Late Late Show with Craig Ferguson. Lennon has appeared in many films including Bad Teacher, Memento, How to Lose a Guy in 10 Days, Transformers: Age of Extinction, and I Love You, Man, for which he and co-star Paul Rudd were nominated for a 2009 MTV Movie Award for Best Kiss. In two of Christopher Nolan's films, Memento (2000) and The Dark Knight Rises (2012), Lennon played a doctor.
Lennon's voice acting work includes Kim Possible, Bob's Burgers, Archer, Planet Sheen in which he played the character of Pinter, and Rock Paper Scissors in which he voiced one of the titular characters, Paper. He played Scribble in Secret of the Wings and Tinker Bell and the Legend of the NeverBeast. He was the voice of Eddie the Shipboard Computer in the film version of The Hitchhiker's Guide to the Galaxy and the voice of Fearless Leader in the 2014 DreamWorks short film version of Rocky and Bullwinkle. He also voiced Munk on Dawn of the Croods and the voice of Chief O'Hara in the Warner Brothers animated film Batman: Return of the Caped Crusaders.
Lennon was a producer of the 2013–2017 late-night panel game show, @midnight, hosted by Hardwick; Lennon appeared 17 times on the show as a panelist/contestant. He won the show seven times. He played Felix Unger in the 2015–17 television series reboot of The Odd Couple opposite Matthew Perry, who played Oscar Madison. In 2016, he co-starred as a scientist in Paramount Animation's Monster Trucks and began a recurring role on the Fox action sitcom Lethal Weapon as Leo Getz, a character which was previously portrayed on film by Joe Pesci. At the 2016 People's Choice Awards ceremony, Lennon participated in an on-stage sketch parodying a recent gaffe by Steve Harvey at the Miss Universe 2015 pageant. In 2020 and 2021, he had a recurring role in Supergirl's fifth and sixth seasons as Mr. Mxyzptlk, taking over from Peter Gadiot.
In 2020, Lennon reprised his role as Lieutenant Jim Dangle in the seventh season of Reno 911! which aired on Quibi. He appeared in the 2021 film Reno 911! The Hunt for QAnon. The eighth season of the series, now titled Reno 911! Defunded, premiered on The Roku Channel in February 2022. In 2023, he was cast in the Zoey 101 reboot, Zoey 102. The film was released on July 27, 2023, on Paramount+.
