Griffes was born in Elmira, NY. In 1907, he became director of music studies at the Hackley School for boys in Tarrytown, New York, a post which he held until his early death thirteen years later.
His most famous works are the White Peacock, for piano (1915, orchestrated in 1919); his Piano Sonata (1917–18, revised 1919); a tone poem, The Pleasure Dome of Kubla Khan, after the fragment by Coleridge (1912, revised in 1916), and Poem for Flute and Orchestra (1918).
Griffes kept meticulous diaries, some in German, which chronicled his musical accomplishments from 1907 to 1919, and also dealt honestly with his homosexuality, including his regular patronage of the Lafayette Place Baths and the Produce Exchange Baths.
Charles Tomlinson Griffes was drawn into the gay world by the baths not just because he had sex there, but because he met men there who helped him find apartments and otherwise make his way through the city, who appreciated his music, who gave him new insights into his character, and who became his good friends. The gay world became a central part of his everyday world, even though he kept it hidden from his nongay associates.
— George Chauncey, Gay New York 1995
During his time as a student in Berlin he was devoted to his "special friend" Emil Joèl (aka "Konrad Wölcke"). In later life, he had a long term relationship with John Meyer (biographer Edward Maisel used the pseudonym Dan C. Martin), a married New York policeman.
He died of influenza in New York City during the worldwide pandemic at the age of 35.