Knoxville was born Philip John Clapp Jr. in Knoxville, Tennessee. His father, Philip Clapp Sr., was a tire/car salesman, and his mother, Lemoyne Clapp (née Houck), taught Sunday school. Knoxville credits a copy of Jack Kerouac's On the Road, given to him by his cousin, singer-songwriter Roger Alan Wade, with giving him the acting bug. After graduating from South-Doyle High School in 1989 in Knoxville, he moved to California to become an actor. In the beginning, Knoxville appeared mostly in commercials and made several minor appearances as an extra. When the "big break" he sought eluded him, he decided to create his own opportunities by writing and pitching article ideas to various magazines. An idea to test self-defense equipment on himself captured the interest of Jeff Tremaine's skateboarding magazine Big Brother, and the stunts were filmed and included in Big Brother's "Number Two" video.
Knoxville is responsible for many of the ideas in Jackass, and is often seen as the de facto leader of the crew. The show also stars Jeff Tremaine, Sean Cliver, Joe Sperry (Spoezy), and Dave Carnie who produced a pilot that used footage from Big Brother and Bam Margera's CKY videos. With help from Tremaine's friend, film director Spike Jonze, they pitched a series to various networks. A deal was made with MTV and Jackass was born. Knoxville also participated in the Gumball 3000 for Jackass along with co-stars Steve-O, Chris Pontius, Jackass director Jeff Tremaine, and producer Dimitry Elyashkevich. Prior to Jackass premiering on MTV, Knoxville and company turned down an offer to perform their stunts for Saturday Night Live on a weekly basis, though Knoxville later hosted a 2005 episode of the show.
Knoxville has been in several feature films, most notably starring opposite Seann William Scott in Jay Chandrasekhar's adaptation of The Dukes of Hazzard. He starred in Jackass: The Movie, Jackass Number Two, and Jackass 3D (which marked the 10th anniversary of the franchise). He played a two-headed alien in the 2002 film Men in Black II. Knoxville also worked with John Waters in A Dirty Shame in 2004, and appeared as a supporting character to The Rock in Walking Tall in the same year. He starred in Katrina Holden Bronson's Daltry Calhoun in 2005, and in The Ringer as an office worker who pretends to be disabled and joins the Special Olympics to pay for surgery for his office's janitor. He starred in the movie Lords of Dogtown as Topper Burks, made a minor appearance in the 2000 movie Coyote Ugly, and was featured as a guest voice on two episodes of King of the Hill.
Knoxville appeared in the John Madden-directed adaptation of Elmore Leonard's novel, Killshot, however his character was subsequently removed from the final cut of the film. He guest-starred in a Season 3 episode "Prank Wars" on Viva La Bam, in which he and Ryan Dunn trashed Bam Margera's Hummer and performed other pranks. He also voiced himself in an episode of Family Guy. Knoxville also co-produces The Dudesons in America and the now-canceled Nitro Circus on MTV. In 2010, Knoxville hosted a three-part online video for Palladium Boots titled Detroit Lives. The videos focus on the resurgence of creativity in Detroit. Knoxville guest starred as the voice of Johnny Krill, an extreme sports enthusiast, in "Extreme Spots", a 2012 episode of SpongeBob SquarePants. Knoxville voiced Leonardo in the 2014 film, Teenage Mutant Ninja Turtles. He was not asked to return for the sequel.
Knoxville has a production company called Dickhouse Productions, which he owns and operates with Jeff Tremaine and Spike Jonze of the Jackass franchise. Dickhouse projects include The Birth of Big Air (2010), a documentary about Mat Hoffman that was part of ESPN's 30 for 30 series, and The Wild and Wonderful Whites of West Virginia (2010), both of which have been picked up by Tribeca Films.
In May 2014, Knoxville (along with Jackass Executive Producer/H.M.F.I.C. Derek Freda) formally announced the formation of a new production company called 'Hello Junior', which will continue Knoxville's now-longstanding relationship with Paramount Pictures, who have signed an exclusive two-year first-look deal with Knoxville and 'Hello Junior' in the wake of the massive success of Bad Grandpa in late 2013. Knoxville was quoted as saying, "I am over the damn moon about continuing an amazing partnership with Paramount Pictures," he said. "I have many more films to make and bones to break. I am glad I will be doing it for Paramount."
Knoxville married Melanie Lynn Cates on May 15, 1995. They have a daughter, Madison (born 1996). His daughter can be heard in the credits for Jackass Number Two, is seen in "The Making of Jackass Two" on the special features on the DVD, and was seen in the credits of Jackass 3D, punching Tremaine with a boxing glove. After 11 years of marriage, the couple separated in July 2006. Knoxville filed for divorce on July 3, 2007. The marriage was legally ended in March 2008, with final divorce arrangements settled in July 2009.
On August 18, 2009, Knoxville announced that he and his girlfriend Naomi Nelson were expecting a baby. Nelson gave birth to a son, Rocko Akira Clapp, on December 20, 2009 in Los Angeles. Knoxville and Nelson married on September 24, 2010. Nelson gave birth to a daughter, Arlo Lemoyne Yoko Clapp, on October 6, 2011, in Los Angeles.
On January 15, 2009, at the Los Angeles International Airport security workers discovered an inert grenade in his carry-on; he was detained and was cited for carrying a prohibited item into the airport. He was released following the investigation when it was determined that the item was a prop from a commercial, and that an assistant had packed his bag for him.
On February 4, 2009, Knoxville explained on The Howard Stern Show how he tore his urethra during a stunt for Nitro Circus explaining how he had to flush it twice daily. He said this was done by "sticking a tube into his penis all the way up to his bladder", referring to the practice of urinary catheterization. Knoxville said the process prevented scar tissue from forming.