Caine began playing piano at seven and studied with French jazz pianist Bernard Peiffer at 12. He later studied at the University of Pennsylvania where he came under the tutelage of George Crumb. He also gained a greater familiarity with classical music in this period and worked at clubs in Philadelphia.
He played professionally after 1981, and by 1985 had his recording debut with the Rochester-Gerald Veasley band. In the 1980s he moved to New York City where he lives now. He also appeared on a klezmer album with Mickey Katz and played with modern jazz musicians Don Byron and Dave Douglas.
Caine, who has recorded 16 albums, is celebrated for his eclectic and inventive interpretations of the classical repertoire. His 1997 jazz tribute to Gustav Mahler received an award from the German Mahler Society, while outraging some jury members. Caine has also reworked Bach's Goldberg Variations, Beethoven's Diabelli Variations, as well as Wagner and Mozart.
In 2001 he teamed up with drummer Zach Danziger to conceive an original project fusing live jungle and drum'n'bass beats with fusion jazz called "Uri Caine Bedrock 3", they have toured worldwide including a New York based Dj called Dj Olive. Also in 2001 he released with Ahmir "?uestlove" Thompson (drum player with internationally acclaimed hip hop band The Roots), and Christian McBride an eclectic album called The Philadelphia Experiment which contains jazz, funk, instrumental hip hop and jazz fusion. This album was produced by Aaron Levinson, and features excellent collaborations such as Pat Martino on guitar and Jon Swana on trumpet. In 2005, Caine was named Composer-in-Residence of the Los Angeles Chamber Orchestra through the 2008–2009 Season. His father is Burton Caine, a professor at Temple Law School.