Quasthoff was born in Hildesheim with serious birth defects caused by his mother's exposure during pregnancy to the drug thalidomide, which was prescribed as an antiemetic to combat her morning sickness.

Quasthoff was denied admission to the Hochschule für Musik, Theater und Medien Hannover, owing to his physical inability to play the piano, rather than a lack of skill required for entry to the conservatory.

In 2003, he made his staged operatic debut as Don Fernando in Beethoven's Fidelio at the Salzburg Festival, conducted by Simon Rattle.

[10] As artist-in-residence at the Barbican Hall,[11] London, Quasthoff invited some of his favourite fellow artists in a series under the title Die Stimme (The Voice, also the name of his autobiography) which marked his 50th birthday.

He cited various reasons such as illness, the strains of touring, and the death of his brother Michael from lung cancer.

He won the Grammy Award for Best Classical Vocal Performance in 2000, for his recording with Anne Sofie von Otter of Mahler's Des Knaben Wunderhorn, along with the Berlin Philharmonic conducted by Claudio Abbado.

His recordings of the songs of Brahms, Liszt and Schubert accompanied by pianist Justus Zeyen were nominated for the Grammy in 2000 and 2001.

Quasthoff won the Grammy Award for Best Classical Vocal Performance for the third time in 2006 with Rainer Kussmaul, the Berlin Baroque Soloists and the RIAS Chamber Choir in their recording of J. S. Bach: Cantatas.

In a 2003 interview, Quasthoff revealed that he is an active political thinker, is a socialist, and was opposed to the Iraq War.