Muti initially learned piano and violin under his father, a physician. He attended the Verdi Conservatory in Milan, studying 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 1973 he became principal conductor of London's New Philharmonia, a post he retained until 1982. Longtime Philadelphia music director Eugene Ormandy effectively selected Muti as his successor in 1980. Muti's tenure in Philadelphia was marked by cool relations with the orchestra and the press, 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.
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. In opera, Muti has tended to focus on Italian repertory, using critical editions of scores and discouraging singers from indulging in traditional interpolations.
Larger and more Italian-style controversy, indeed, awaited Muti in La Scala, where he clashed artistically with general manager Carlo Fontana, succeeded in having Fontana dismissed in favor of his own choice, but then faced a rebellion from the players. He resigned his post in April of 2005, but has remained immensely influential in opera through his close association with the Salzburg Festival, where he has conducted a large number of operatic performances.
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, where in 2011 he led not only the chorus, but also the audience in a rendition of "Va pensiero," a chorus from Verdi's Nabucco (and something of an Italian national hymn), in a protest against arts budget cuts by the government of prime minister Silvio Berlusconi. In Chicago, Muti ingratiated himself with the city's sports-mad populace by donning a Chicago Blackhawks jersey during the team's 2013 championship run. Muti has remained a popular guest conductor internationally, and in 2018 he returned for his fifth turn with the baton at the Vienna Philharmonic New Year's Concert. Muti is married to festival director Maria Cristina Mazzavillani, and the couple has three children.