Frank O'Hara, the son of Russell Joseph O'Hara and Katherine (née Broderick) was born on March 27, 1926, at Maryland General Hospital, Baltimore and grew up in Grafton, Massachusetts. He attended St. John's High School in Worcester. He grew up believing he had been born in June, but in fact had been born in March, his parents having disguised his true date of birth because he was conceived out of wedlock. He studied piano at the New England Conservatory in Boston from 1941 to 1944 and served in the South Pacific and Japan as a sonarman on the destroyer USS Nicholas during World War II.

With the funding made available to veterans he attended Harvard University, where artist and writer Edward Gorey was his roommate. Although O'Hara majored in music and did some composing, his attendance was irregular and his interests disparate. He regularly attended classes in philosophy and theology, while writing impulsively in his spare time. O'Hara was heavily influenced by visual art and by contemporary music, which was his first love (he remained a fine piano player all his life and would often shock new partners by suddenly playing swathes of Rachmaninoff when visiting them). His favorite poets were Arthur Rimbaud, Stéphane Mallarmé, Boris Pasternak and Vladimir Mayakovsky. While at Harvard, O'Hara met John Ashbery and began publishing poems in the Harvard Advocate. Despite his love of music, O'Hara changed his major and graduated from Harvard in 1950 with a degree in English.

He then attended graduate school at the University of Michigan in Ann Arbor. While at Michigan, he won a Hopwood Award and received his M.A. in English literature in 1951. That autumn O'Hara moved into an apartment in New York City with Joe LeSueur, who would be his roommate and sometime lover for the next 11 years. It was in New York that he began teaching at The New School.

Known throughout his life for his extreme sociability, passion and warmth, O'Hara had hundreds of friends and lovers throughout his life, many from the New York art and poetry worlds. Soon after arriving in New York, he was employed at the front desk of the Museum of Modern Art and began to write seriously.

O'Hara was active in the art world, working as a reviewer for Artnews, and in 1960 was Assistant Curator of Painting and Sculpture Exhibitions for the Museum of Modern Art. He was also friends with the artists Willem de Kooning, Norman Bluhm, Larry Rivers and Joan Mitchell.

In the early morning hours of July 24, 1966, O'Hara was struck by a dune buggy on the Fire Island beach. He died the next day of a ruptured liver. O'Hara was buried in Green River Cemetery on Long Island. The painter Larry Rivers, a longtime friend and lover of O'Hara's, delivered the eulogy.