As a teenager, Claypool was turned on to rock music such as Led Zeppelin and Jimi Hendrix by classmate Kirk Hammett (of Metallica fame). He picked up the bass at the age of fourteen, learning scales and technique in his school jazz band. After graduating high school, Claypool played in a local cover band called the Tommy Crank Band; there, he was able to hone his skills and develop his famous slap technique through listening to Stanley Clarke and Larry Graham. He also bought his first Carl Thompson bass, his trademark four string piccolo. (He now owns six, including a multi-wood fretless 6-string called the Rainbow Bass.)
In the late 80s, Claypool played in the band Blind Illusion with future Primus guitarist Ler Lalonde. Primus began as something of a side project with Claypool's friends Todd Huth and Jay Lane; they released their first demo tape, Sausage, around 1989. However, Huth and Lane left the band soon after to pursue personal matters. Claypool replaced them with Lalonde and drummer Tim Alexander. Primus' first album, the live cut Suck On This, was released in 1990 on Claypool's Prawn Song record label (a parody of Led Zeppelin's Swan Song Records). They gained a cult following in their hometown of Berkeley, CA, and later that year, released their first studio album, Frizzle Fry. Primus began to gain popularity, especially after the release of Sailing the Seas of Cheese on Interscope in 1991. The first single, Jerry was a Racecar Driver, brought Primus' goofy, heavy, unique sound to the masses. The reaction to the album was good enough that 1993's Pork Soda debuted in the top 10. Primus earned a headlining spot on the Lollapalooza tour that year. 1994 saw the release of Riddles Are Abound Tonight (under the name Sausage), a reunion of the original Primus lineup (Claypool-Huth-Lane). Tales From The Punchbowl was released in 1995, scoring a hit with the western-flavored Wynona's Big Brown Beaver. Alexander left the band in 1996; he was replaced by Brian Mantia of Praxis and Buckethead. Claypool released the album Highball with the Devil that year under the name Les Claypool and the Holy Mackerel.
1997's Brown Album was a departure from "original" Primus, with a blander production and spacier, more experimental songs. (Interestingly, Tom Waits names it as his favorite Primus album, though some fans openly hated it). The cover album Rhinoplasty was released in 1998, and in 1999, Primus' latest album, Antipop, was released. It features such musicians as Tom Morello, James Hetfield, Tom Waits, Matt Stone (co-creator of South Park), and Fred Durst. After touring that year, Primus went on an indefinite hiatus; but that didn't stop Claypool.
In 2000, Claypool formed the Les Claypool Frog Brigade, a jam-rock band much like Phish or String Cheese Incident. This allowed him to return to his musical roots, playing songs by bands like Pink Floyd, King Crimson, and the Beatles. In addition to two live albums (one being an exact cover of Pink Floyd's Animals), the Frog Brigade has released one studio album, 2002's Purple Onion. Claypool has also collaborated with Trey Anastasio and Stewart Copeland in jam-rock project Oysterhead.
Lengthening his jam band streak, in 2003 Claypool put out a manic, frantic record with Buckethead, Bernie Worrel, and former Primus drummer Brain under the ominous band name, Colonel Claypool's Bucket of Bernie Brains, whose concerts pushed the improvisational envelope by preparing no material and not rehearsing beforehand.
In late 2003 Claypool reunited with original Primus drummer Tim Alexander and guitarist Larry LaLonde to record a DVD/EP called Animals Should Not Try to Act Like People, which Claypool described as the first DVD with supplementary music, as opposed to the contrary. The band staged a two month tour in which they performed two sets per show, the second consisting of their 1991 release Sailing the Seas of Cheese in its entirety.