Uri Caine was born June 8, 1956, in Philadelphia, the son of Temple Law School professor Burton Caine (1928–2023) and poet Shulamith Wechter Caine. He began playing piano at seven and started lessons at twelve with the French jazz pianist Bernard Peiffer. He went on to the University of Pennsylvania, where he studied composition with George Rochberg and George Crumb while deepening his classical training and playing Philadelphia's club scene as a teenager and young adult.

Caine turned professional after 1981 and made his recording debut in 1985 with the Rochester-Gerald Veasley band. He relocated to New York City in the 1980s, where he still lives, and released his debut as a leader, Sphere Music (1993, JMT), in 1992 — a Thelonious Monk-rooted session that opened his long musical partnership with clarinetist Don Byron. Byron and Caine worked together again the same year on Byron's own Plays the Music of Mickey Katz (1993). Caine's second leader album, Toys (1995, JMT), turned to Herbie Hancock's book and brought in a young trumpeter named Dave Douglas — the beginning of a collaboration that would resurface, transformed, two decades later.

By the late 1990s Caine had found the project that would define his public identity: radical, large-ensemble jazz reworkings of the classical canon. Urlicht / Primal Light (1997, Winter & Winter), his reimagining of Gustav Mahler's Second and Fifth Symphonies and songs from Kindertotenlieder, won the Toblacher Komponierhäuschen award from the International Gustav Mahler Society for the year's most original Mahler recording — a decision that reportedly split the judging panel between admirers and traditionalists offended by a jazz pianist rearranging Mahler. Caine followed it with two more large-scale classical projects for Winter & Winter: The Goldberg Variations (2000), a double-CD recorded for the 250th anniversary of Bach's death and scored for an ensemble stretching from a period-instrument viol consort to a Hammond organ, and Diabelli Variations (2002), commissioned by the Kempen Musik Festival and premiered in the Paterskirche in Kempen, Germany, with Caine alternating between a reproduction fortepiano and the historic-instrument orchestra Concerto Köln. The Othello Syndrome (2008, Winter & Winter), his response to Verdi's opera Otello featuring Philadelphia soul singer Bunny Sigler, earned Caine and the Uri Caine Ensemble a Grammy nomination for Best Classical Crossover Album at the 51st Annual Grammy Awards in 2009.

Caine never confined himself to the classical-reinterpretation lane. The Philadelphia Experiment (2001, Ropeadope/Rykodisc) united him with bassist Christian McBride and drummer Ahmir "Questlove" Thompson of the Roots in a jazz-funk-hip-hop hybrid that AllMusic called a defining document of that crossover moment; the trio reunited for a rare live performance at the 2017 Newport Jazz Festival. Around the same period Caine also led Bedrock, a drum-and-bass-inflected fusion project with drummer/programmer Zach Danziger, and began a long-running duo with Sardinian trumpeter Paolo Fresu, documented on the Blue Note albums Things (2006) and Think (2009, with the Quartetto Alborada string quartet). Nigunim (1998, Tzadik), a trio session with Frank London and Lorin Sklamberg exploring Yiddish devotional melodies for John Zorn's Radical Jewish Culture series, and Rio (2001, Winter & Winter), an album of Brazilian songs cut with a Rio de Janeiro rhythm section, further show the range Caine kept moving through even at the height of the Mahler years.

The Dave Douglas connection did not end with Toys. Through the following decade Caine kept turning up as a sideman across Douglas's own leader albums: Stargazer (1997, Arabesque, on piano), Soul on Soul (2000, RCA), The Infinite (2002, on Fender Rhodes), and Strange Liberation (2003, also Fender Rhodes) — a run of five studio dates together, Caine always in Douglas's band rather than the reverse. That accumulated partnership resurfaced as a formal co-billing in the 2010s: Present Joys (2014, Greenleaf Music) paired Caine and Douglas as equal co-leaders for the first time, working through pieces from the Sacred Harp shape-note songbook alongside new Douglas compositions in the same vein; The Guardian called it a highlight of that year in jazz. Douglas and Caine expanded the partnership into a trio on Devotion (2019, Greenleaf Music), adding the veteran drummer Andrew Cyrille. Douglas's own JazzProfiles.com profile covers his career in full and confirms all of these as genuine, Discogs-documented credits rather than one-off session work.

Caine's honors include a term as composer-in-residence with the Los Angeles Chamber Orchestra (2005–2009), a United States Artists Fellowship (2010), and a composer-in-residence appointment at Mannes College (2013–2014). His most ambitious recent large-scale work, The Passion of Octavius Catto (recorded 2018, released 2019 on his own 816 Music label), is an oratorio for jazz quartet, choir, and orchestra commemorating Octavius Catto, the Philadelphia civil-rights leader and educator assassinated in 1871 — a rare instance of Caine turning his classical-jazz synthesis toward American history rather than the European canon. He has continued to record prolifically into the 2020s, with Catbird (2020) and Agent Orange (2023) among his more recent leader dates.

Caine's foundation is dual: rigorous classical training under composers George Rochberg and George Crumb at Penn, layered onto a jazz language built from Monk, Bud Powell-descended stride, and Philadelphia's club scene. What makes his classical-reinterpretation records distinctive, critics and scholars have noted, is that he doesn't merely reharmonize a classical theme in a jazz idiom the way generations of jazz musicians treated the songbook — he shifts wholesale between musical styles inside a single piece, letting klezmer, gospel, tango, and turntablism sit up against the original score rather than blending into it. That postmodern, juxtapositional approach, combined with his Jewish heritage (explicit in Nigunim and his other Radical Jewish Culture-series work for Tzadik) and a restless curiosity that pulled him through hip-hop, Brazilian music, and drum-and-bass alongside Mahler and Verdi, makes him one of the most genre-promiscuous pianist-composers to emerge from the Philadelphia and New York scenes of the 1990s onward.