After studying piano as a child (starting when he was five years old), he began as a teenager to perform with musicians such as Mark Murphy and Jaco Pastorius.

In 1983, after graduating from high school, he began studying piano at the New England Conservatory in Boston, where he performed as a sideman with Dewey Redman, Billy Higgins, Bob Mintzer, Alan Dawson.

[3] Medeski performs in a range of musical styles, from accessible groove based funk and jazz (such as the MMW albums and A Go Go with John Scofield) to more experimental music (including many of John Zorn's projects: Duras: Duchamp, Interzone, Liber Novus, Nova Express, Dreamachines, Templars: In Sacred Blood, At the Gates of Paradise etc.

In 2000, Medeski became a member of The Word, a bluesy gospel style project with members Robert Randolph (pedal steel) from Robert Randolph and the Family Band, brothers Luther Dickinson (guitar) and Cody Dickinson (drums), and Chris Chew (bass) of North Mississippi Allstars.

[6] On July 14, 2006, John Medeski & The Itch performed their debut gig at the All Good Music Festival in Masontown, West Virginia.

The Itch consists of Eric Krasno (guitar) of Soulive and Adam Deitch (drums) with Medeski playing a B3 Organ.

[9] With Either/Orchestra With Spectrum Road (Tony Williams tribute project with Cindy Blackman, Jack Bruce, Vernon Reid)