Nézet-Séguin became the musical director of the Chœur polyphonique de Montréal in 1994 and enrolled at the Conservatoire de musique du Québec the following year. He also studied choral conducting with Joseph Flummerfelt and Hermann Max at Westminster Choir College in Princeton, New Jersey.
At age 22, he succeeded Bernard Uzan as Director of the Opéra de Montréal in 1998. In 1999 and 2000, he conducted the Orchestra of Les Grands Ballets Canadiens in The Nutcracker by Tchaikovsky, as well the chamber orchestra Les Violons du Roy. He has been music director of the Orchestre Métropolitain du Grand Montréal since 2000. Nézet-Séguin considers Charles Dutoit and Carlo Maria Giulini as his greatest inspirations as conductors. His current contract with the Orchestre Métropolitain is through 2010.
His UK conducting debut was with the Northern Sinfonia in the 2005-2006 season. He has since debuted with the London Philharmonic Orchestra (LPO) in March 2007, and with the Scottish Chamber Orchestra in April 2007. In November 2007, the LPO named Nézet-Séguin as their new principal guest conductor, effective with the 2008-2009 season.
In 2005, Nézet-Séguin guest-conducted the Rotterdam Philharmonic Orchestra (RPhO) for the first time, and returned in 2006. In December 2006, the RPhO announced the appointment of Nézet-Séguin as their 11th Principal Conductor, by a unanimous vote, effective with the 2008-2009 concert season. Nézet-Séguin has an initial contract in Rotterdam for 4 years.