George Lewis graduated from Yale University with a degree in philosophy. In the 1970s, he succeeded Rhys Chatham as the music director of The Kitchen. Since 2004, he has served as a professor at Columbia University in New York City, having previously taught at the University of California, San Diego. Lewis is married to koto player Miya Masaoka. They have a son together. In 2002 Lewis received a MacArthur Fellowship.
In addition to his own recordings, he has recorded or performed with musicians including Anthony Braxton, John Zorn, Roscoe Mitchell, Douglas Ewart, Laurie Anderson, Muhal Richard Abrams, Count Basie, Gil Evans, Nicole Mitchell, Karl E. H. Seigfried, Fred Anderson, Conny Bauer, Evan Parker, and Bertram Turetzky. He was also a sometime member of the ICP Orchestra (Instant Composer's Pool).
Lewis has long been active in creating and performing with interactive computer systems, most notably his software called Voyager, which "listens to" and reacts to live performers. Between 1988 and 1990, Lewis collaborated with video artist Don Ritter to create performances of interactive music and interactive video controlled by Lewis’s improvised trombone. Lewis and Ritter presented over 20 performances at venues in North America and Europe, including Festival International de Musique Actuelle de Victoriaville, Verona Jazz Festival, Art Institute of Chicago, The Kitchen (NYC), New Music America 1989 (NYC), The Alternative Museum (NYC), A Space (Toronto), and the MIT Media Lab (Cambridge).
In 2008 Lewis published a book-length history of the AACM titled A Power Stronger Than Itself: The AACM and American Experimental Music (University of Chicago Press).