Metzmacher was born in Hanover Germany to the cellist Rudolf Metzmacher in Hanover. His musical education in piano, music theory and conducting was in Hanover, Salzburg and Cologne, and later joined the Ensemble Modern in 1981 as its pianist. He became the orchestra's conductor in 1985.
His first conducting engagement was in 1987, with Le Nozze di Figaro. In 1994 he gave the premiere of the revised version of Hans Werner Henze's Symphony No. 6, and 1997 he conducted the world premiere of Henze's Symphony No. 9 at the composer's request. From 1997 to 2005, he served as General Music Director of City of Hamburg, which covered the Hamburg State Opera and its Philharmonic Orchestra. He left his post in Hamburg after disputes with the city over funding.
In 2005, he became chief conductor of De Nederlandse Opera. In February 2007, De Nederlandse Opera announced that Metzmacher would step down from his post as DNO's Chief Conductor in 2008. With the start of the 2007-2008 season, he assumed the post of principal conductor of the Deutsches Symphonie-Orchester Berlin.