He was born in Los Angeles, California, where he studied at the University of Southern California under Ingolf Dahl among others. In 1969 he made his conducting debut with the Boston Symphony Orchestra, being called in at the last minute to replace an unwell William Steinberg. He stayed with the Boston ensemble as an assistant conductor until 1974. He was music director of the Buffalo Philharmonic Orchestra from 1971 to 1979, and from 1971 to 1977 conducted the series of Young People's Concerts with the New York Philharmonic.
From 1981 to 1985 he was principal guest conductor of the Los Angeles Philharmonic Orchestra, and from 1988 to 1995 he was principal conductor of the London Symphony Orchestra, becoming principal guest conductor thereafter. In 1995 he became music director of the San Francisco Symphony Orchestra. He is founder of the New World Symphony Orchestra (based in Miami, Florida) which acts as a training ground for young musicians.
Tilson Thomas has conducted a wide variety of music, and is a particular champion of modern American works, recording the complete symphonies of Charles Ives and the premiere recording of Steve Reich's The Desert Music.