He was born in Liverpool, England, and sang in his high school choir. He played the violin and was awarded a scholarship. While studying chemistry and physics at Liverpool University, he studied voice with Austen Carnegie.
He made his operatic debut in Debussy's Pelléas et Mélisande at the Glyndebourne Festival in 1961, and has been prominent in performing and recording the vocal works of Benjamin Britten. These have included the premiere performances of Canticle IV: Journey of the Magi and Death in Venice. The latter part was written specially for him, and involves multiple roles as protagonist to the character of Gustav von Aschenbach. In 1977 he created the role of Lev in Sir Michael Tippett’s The Ice Break at Covent Garden.
He appears regularly with major orchestras and opera companies throughout the world and has a vast discography. Notable recordings include Britten's works and Mahler's Eighth Symphony under Sir Georg Solti on Decca, and Vaughan Williams' vocal works under Sir David Willcocks and the Choir of King's College, Cambridge for EMI.
In 1975, John Shirley-Quirk was made a Commander of the Order of the British Empire.
He was a member of staff at Acton Technical College until 1957 and played a part in events leading to the formation of Brunel College. He is currently on the faculty of the Peabody Conservatory of Music in Baltimore, MD.
Was married to oboist Sara Watkins who died in 1997.