In 1992, at age 30, he became principal conductor of the Orchestra Dell'Accademia Nazionale di Santa Cecilia in Rome for 5 years. In 1997, he became the music director of the Orchestra del Teatro Comunale di Bologna. He has also served as principal guest conductor of the Royal Opera House, Covent Garden. In 2005, alongside Zubin Mehta and Christian Thielemann, Gatti was invited to conduct a concert in commemoration of the fiftieth anniversary of the 1955 reopening and renovation of the Vienna State Opera. His debut at the Bayreuth Festival was in Stefan Herheim's production of Parsifal in 2008.
In 1994, Gatti made his first guest conducting appearance with the Royal Philharmonic Orchestra (RPO), London. He was immediately offered the position of the RPO's principal conductor, and he assumed the post in 1996. Gatti is regarded as having restored the RPO's status on par to the other main London orchestras. During his tenure, in 2004, the RPO acquired its first permanent residency at Cadogan Hall. In 2009, Gatti stepped down as the RPO's principal conductor and became the orchestra's conductor laureate.
Gatti became Music Director of the Orchestre National de France in September 2008. He was chief conductor of the Zurich Opera from 2009 to 2012. In October 2014, the Royal Concertgebouw Orchestra appointed Gatti as its seventh chief conductor, effective in 2016.
In April 2007, Gatti, together with Valery Gergiev, was one of eight conductors of British orchestras to endorse the 10-year classical music outreach manifesto, "BUILDING ON EXCELLENCE: Orchestras for the 21st Century", to increase the presence of classical music in the UK. The program includes free entry to all British schoolchildren to a classical music concert.