Anthony John Medeski was born in Louisville, Kentucky on June 28, 1965 and grew up in Fort Lauderdale, Florida, where his father put him in front of a piano as a toddler and classical lessons began at about five. By his early teens he was working professionally with local dance and theatre companies, and he had found jazz on his own, taking apart the solos of Oscar Peterson, Bud Powell and Cecil Taylor. He studied privately with the pianist Lee Shaw, who taught him harmony and theory, attended Pine Crest School, bought a Fender Rhodes and started a fusion trio called Emergency. South Florida gave him his first professional jazz work, including gigs with the singer Mark Murphy and with Jaco Pastorius; the story he has repeated since is that he was invited to join Pastorius for a 1981 tour of Japan and that his mother decided he was too young to go.

He won a National Endowment for the Arts award in 1982 and moved to Boston the following year to study classical piano with Leonard Shure at the New England Conservatory. By his second year he had crossed into Ran Blake's Third Stream department and was working with George Russell, Dave Holland and Joe Maneri. The more consequential education happened on bandstands: he played alongside the drummer Bob Moses, backed visiting artists including Dewey Redman, Billy Higgins and Alan Dawson, and took up the Hammond B-3 in earnest while working nightly with the Boston roots singer Mr. Jellybelly. He also joined Russ Gershon's Either/Orchestra, appearing on its first three albums between 1990 and 1996, and played in the Ken Schaphorst Big Band and with the Jazz Composers Alliance. A run of regular dates at the Village Gate in New York between 1988 and 1990 finally pulled him south for good.

Moses introduced him to the drummer Billy Martin and the bassist Chris Wood, and in 1991 the three formed Medeski Martin & Wood. Their first record, Notes from the Underground (1992), is an acoustic piano trio album with a horn section drawn from the same Boston and New York circle, including Thomas Chapin and Steven Bernstein. Almost immediately Medeski began adding electric keyboards, running a Wurlitzer through distortion pedals and moving between Hammond organ, clavinet and Mellotron, while Wood alternated upright and electric bass and stuffed paper behind his strings for a snare effect. It's a Jungle in Here (1993), Friday Afternoon in the Universe (1995) and Shack-man (1996), all for Gramavision, rebuilt the soul-jazz organ trio around hip-hop rhythm and open improvisation. A guest slot with Phish on October 14, 1995 brought the band an audience that no jazz club could have supplied, and the trio spent the rest of the decade moving between the downtown improvisers' world and the jam-band circuit without belonging entirely to either. In 1998 they signed to Blue Note, where they stayed until 2005, and they backed John Scofield for a whole album, A Go Go, which reached far more listeners than anything they had made under their own name.

Alongside the trio, Medeski became one of the busiest keyboard players in downtown New York. John Zorn used him on nine of the twenty-five pieces on Bar Kokhba (1996) and gave him the organ part on Duras: Duchamp (1997), the start of an association that has run for thirty years through Interzone, Nova Express, Simulacrum, Chaos Magick and the Bagatelles. He played on Marc Ribot's The Prosthetic Cubans (1998), on Frank London's The Debt (1997) and on The Klezmatics' Possessed the same year, and he produced as well as played on the Dirty Dozen Brass Band's Buck Jump (1999). His organ turns up on two tracks of Morphine's The Night and on records by Cibo Matto, David Byrne and Iggy Pop. In 2000 he and the North Mississippi Allstars recruited a then-unknown pedal steel player, Robert Randolph, for The Word, an instrumental sacred-steel band whose self-titled debut Medeski produced in 2001. Medeski Martin & Wood also contributed to the Red Hot Organization's Duke Ellington tribute Red Hot + Indigo that year.

The trio left Blue Note after End of the World Party (Just in Case) (2004) and set up their own label, Indirecto, which they used for the four-album Scofield quartet, billed as Medeski Scofield Martin & Wood, and for the Radiolarians series of 2008 and 2009, made by inverting the usual order: write on the road, play the material live for months, and record it only afterwards. Medeski's own projects multiplied. He and Billy Martin made the organ-and-drums duo Mago (2007); he sat in with Steven Bernstein's Sex Mob at Willisau in 2006 for a live album; he shared the billing on Heaven on Earth (2009) with James Carter, Christian McBride, Adam Rogers and Joey Baron; and in 2010 he played a two-piano concert in Albany with Lee Shaw, his first teacher. In 2012 he joined Jack Bruce, Vernon Reid and Cindy Blackman in Spectrum Road, a quartet built on the repertoire of Tony Williams Lifetime. His first solo record, A Different Time (OKeh, 2013), is a quiet acoustic piano album, and the same year he took the piano chair in Matt Wilson's quartet for Gathering Call.

Since then he has worked mostly through a set of standing groups. Hudson, formed in 2017 with Jack DeJohnette, John Scofield and Larry Grenadier, took its name from the river all four live near and its repertoire from a mix of originals and songs of the late 1960s. John Medeski's Mad Skillet, whose debut appeared in 2018, is a New Orleans quartet with the guitarist Will Bernard and two members of the Dirty Dozen Brass Band, the sousaphonist Kirk Joseph and the drummer Terence Higgins. Omnisphere, also 2018, set Medeski Martin & Wood against the chamber orchestra Alarm Will Sound. A trio with the drummer Ben Perowsky and the reed player Chris Speed released Upstream in 2019, and another with Jeff Cosgrove and Jeff Lederer made History Gets Ahead of the Story in 2020. Crawlspace: An Electro-Acoustic Fantasy (Tzadik, 2021) is a solo album for a room full of vintage keyboards. In 2023 he composed and performed the score for the Showtime series The Curse, created by Nathan Fielder and Benny Safdie, a commission that came to him because the producers wanted something in the spirit of Alice Coltrane's Turiya Sings. Mississippi Murals (2024), improvised in front of Walter Inglis Anderson's murals on the Gulf Coast, and Julian Lage's Scenes from Above (Blue Note, 2026), on which he plays throughout, are his most recent released work. He lives in the Hudson Valley and is listed as a Steinway artist.

Medeski's signature is that he treats the whole history of the keyboard as one instrument. Within a single piece he will move from Steinway grand to Hammond B-3 to clavinet to Mellotron to melodica, and the sleeve of Uninvisible lists twelve keyboards under his name alone, from a Hammond A100 to a Sequential Circuits Pro-One. That range is not a collector's habit but a compositional one: the choice of instrument does the work that orchestration does for a horn writer, and it is what lets Medeski Martin & Wood sound like a soul-jazz organ trio on one track and a free-improvising acoustic group on the next. The foundation underneath it is unusually formal, a classical training under Leonard Shure and a Third Stream education under Ran Blake, George Russell and Joe Maneri, and it shows in how much of his playing is about voicing and colour rather than line. Two currents run through everything: the greasy, blues-rooted organ tradition he learned playing nightly in Boston roots bands, and the abstraction of the downtown New York scene, where John Zorn has used him for thirty years precisely because he can play a written chamber part and then improvise freely off it. Critics have generally credited Medeski Martin & Wood with carrying jazz to a rock audience without diluting it, and the trio's own term for the result, avant-groove, describes the balance better than any genre label. His own account of his beginnings puts Oscar Peterson first, with Bud Powell and Cecil Taylor close behind, which is roughly the span his playing still covers.