Muti initially learned piano and violin under his father, a physician. The boy later enrolled at the San Pietro Conservatory in Naples, where he studied composition with Jacopo Napoli and Nino Rota
(some of whose film music Muti would record decades later for Sony Classical), and piano (his major subject) with Vincenzo Vitale. Following a stint in philosophy at Naples University, Muti transferred to the Verdi Conservatory in Milan, to study composition with Bruno Bettinelli and conducting with Antonino Votti.
Muti won the Guido Cantelli Conducting Competition in 1967. This led to his professional debut with the RAI Orchestra in 1968. In 1970 he was named principal conductor of the Florence May Festival (he was promoted to artistic director in 1977), and the following year became principal conductor at the Teatro Communale in Florence.
In 1973 he became principal conductor of London's New Philharmonia, a post he retained until 1982 (being made music director in 1979). Longtime Philadelphia music director Eugene Ormandy
effectively selected Muti as his successor in 1980, and Muti soon gave up his posts in Florence and London.
Muti's tenure in Philadelphia was marked by cool relations with the orchestra and the press; all parties kept a safe distance from each other, as Muti tightened the orchestra's ensemble while retaining its tonal warmth. He made major changes in programming practices, offering concert operas and commissioning works by such tough modernists as Berio, Davidovsky, Kirchner, and Ran, as well as more iconoclastic Americans such as Bolcom and Rouse. His interests in twentieth century material also extended to the works of Britten, Dallapiccola, Hindemith, Ligeti, Prokofiev, and especially Shostakovich.
Muti's heart remained with opera, and in 1986 he agreed to become music director of La Scala (and principal conductor of the La Scala Philharmonic the following year). Muti left Philadelphia in 1992, rarely to return, although his tenure there was relatively free of the public contention that would be routine in the volatile climate of La Scala. In opera, Muti has tended to focus on Italian repertory, using critical editions of scores and discouraging singers from indulging in traditional interpolations.
Since 2010, Muti has been the music director of the Chicago Symphony Orchestra, as well as the music director of the Teatro dell'Opera di Roma.