On October 22, 1969, he was called to replace William Steinberg during a Carnegie Hall concert, repeating the circumstances of Leonard Bernstein's sensational debut 26 years earlier with nearly identical results: Tilson Thomas was catapulted into the top ranks of American conductors. In 1970 he was appointed associate conductor of the BSO, then principal guest conductor until 1974. He served as music director of the Buffalo Philharmonic Orchestra (1971-1979), principal guest conductor of the Los Angeles Philharmonic (1981-1985), and principal conductor of the London Symphony Orchestra (1988-1995). In 1995, Tilson Thomas was appointed the 11th music director of the San Francisco Symphony Orchestra. Together, he and the orchestra went on international tours, won a Grammy for their 1997 recording of Prokofiev's Romeo and Juliet, created the cross-platform educational program Keeping Score, and launched their own label in 2001. In 1988, recognizing a need for music graduates to gain experience, he created the New World Symphony. Membership in that ensemble is now considered a desirable first step in an orchestral career. Tilson Thomas also spends time composing. He wrote From the Diary of Anne Frank on commission from UNICEF in 1990 (the premiere was narrated by actress Audrey Hepburn). In 1995, he was commissioned by Hiroshima, Japan, to write Shówa/Shoáh for the 50th anniversary of the bombing of the city.
Tilson Thomas is a Chevalier dans l'ordre des Arts et des Lettres of France, and in 2010 he received the National Medal of Arts, the highest artistic award given in the United States. By 2014, he had received 12 major Grammy Awards in the categories of Best Orchestral Performance, Best Choral Performance, and Best Classical Album.
Tilson Thomas' other conducting credits include a performance at the helm of the YouTube Symphony Orchestra in 2011. Beginning in 2006 with a recording of Mahler's Symphony No. 5, many of Tilson Thomas' performances with the San Francisco Symphony have been recorded for release on the orchestra's own label. These included a complete cycle of Robert Schumann's symphonies, released in 2017. That year, Tilson Thomas announced that he would step down as the orchestra's conductor in 2020.