Mayer is the son of a touring musician and began his career as a drummer at an early age, receiving his first drum set at the age of two. Having taught himself throughout his childhood, he broke out into the professional music scene at the age of 18, joining the Monty Alexander group. Touring with the group launched him into the major jazz music scene, and he has played at the North Sea Jazz Festival, Montreux, Nice, and Athens etc., which culminated with his gigging with jazz-greats such as Dizzy Gillespie and Nina Simone. Eventually, after playing with a great variety of artists, Mayer moved away from jazz and into Drum 'n' Bass electronica.

Jojo Mayer is known for bringing together jazz, drum and bass, jungle, and other influences. He is also famous for his ability to play the rhythms of programmed jungle drum 'n' bass music on acoustic drums, terming this technique "reverse engineering", a phrase borrowed from computing. He executes this approach using various methods such as the Heel-toe bass drum technique, the Moeller stroke, and the "pull-out" or "push-pull" accent which takes the beat on the rebound. Using these techniques, he can play beats at astonishing speeds. A few of his main influences are Tony Williams, Jack DeJohnette and Buddy Rich.

He is the leader of live electronica trio Nerve, which he founded in 1997.

He played with the guitarist David Fiuczynski in the avant-garde pop rock band Screaming Headless Torsos and in the fusion jazz band, Intergalactic Maiden Ballet.