Luisi was born in Genoa. He attended the Conservatorio Nicolò Paganini and was a student of Memi Schiavina. After receiving his degree in piano studies, he continued piano instruction with Aldo Ciccolini and Antonio Bacchelli.
Luisi developed an interest in conducting while working as a piano accompanist, and he studied conducting at the conservatory in Graz with Milan Horvat. He worked at the Graz Opera as an accompanist and conductor. His first conducting appearance was in Italy in 1984. From 1990 to 1995, he was principal conductor of the Graz Symphony Orchestra. From 1995 to 2000, he served as Artistic Director and Chief Conductor of the Tonkünstlerorchester in Vienna. From 1996 to 1999, he was one of three main conductors (Hauptdirigenten) of the MDR Symphony Orchestra (Mitteldeutscher Rundfunk Sinfonieorchester) in Leipzig, along with Marcello Viotti and Manfred Honeck. From 1999 to 2007, he was sole principal conductor of the MDR orchestra. He was the principal conductor of l'Orchestre de la Suisse Romande from 1997 to 2002.
In January 2004, Luisi was named chief conductor of both the Staatskapelle Dresden and of the Semperoper, Dresden. He assumed both posts in September 2007. With the Staatskapelle Dresden, Luisi conducted commercial recordings of music by Richard Strauss and Anton Bruckner. Luisi was originally scheduled to step down as chief conductor of the Staatskapelle Dresden in 2012, at the expiration of his contract. However, he resigned from both Dresden posts in February 2010, with immediate effect, after reports that the Staatskapelle's management had secured a contract with the ZDF network for a scheduled televised concert on New Year's Eve, 2010 with Christian Thielemann as conductor, without consulting him at all in his capacity as the orchestra's GMD.
Luisi served as Chief Conductor of the Vienna Symphony from 2005 through the 2012-13 season. He became Generalmusikdirektor (General Music Director) of the Zurich Opera in 2012, which also includes orchestral concert work with the opera orchestra under the name of the Philharmonia Zurich. Luisi first conducted the Danish National Symphony Orchestra in 2010. In August 2014, the orchestra announced the appointment of Luisi as its next principal conductor, effective in 2017, with an initial contract through 2020. In January 2016, the Opera di Firenze announced the appointment of Luisi as its next music director, the first conductor to hold that title with the company, and in parallel, as director of the Maggio Musicale Fiorentino, as of April 2018, with an initial contract of 5 years.
In the United States, Luisi made his Metropolitan Opera conducting debut in March 2005, with Giuseppe Verdi's Don Carlos. In April 2010, Luisi was named the Met's principal guest conductor, for an initial contract of three years, effective with the 2010-2011 season. Luisi is the second conductor to be named to this post at the Metropolitan Opera, after Valery Gergiev. He was elevated to the post of Principal Conductor in September 2011, when Music Director James Levine withdrew from his scheduled fall 2011 performances. Luisi is scheduled to stand down from this post at the close of the 2016-2017 season.