Born in Cincinnati, Ohio, he largely grew up in Chicago. White attended the prestigious Cranbrook School in Bloomfield Hills, Michigan as a boy, then studied Chinese at the University of Michigan. He later worked in New York as a journalist. From 1983 to 1990 he lived in France.

Incestuous feelings existed in White's family; his mother was attracted to him. White spoke of his own sexual attraction to his father in an interview: "I think with my father he was somebody who every eye in the family was focused on and he was a sort of a tyrant and nice-looking, the source of all power, money, happiness, and he was implacable and difficult. He was always spoken of in sexual terms, in the sense he left our mother for a much younger woman who was very sexy but had nothing else going for her. He was a famous womanizer. And he slept with my sister!"

White's best-known work is A Boy's Own Story, the first volume of an autobiographical-fiction series that continued with The Beautiful Room Is Empty and The Farewell Symphony, describing stages in the life of a gay man from boyhood to middle age. Several characters in these latter two novels are recognizably based on well-known individuals from White's New York-centered literary and artistic milieu. White was a member of The Violet Quill, a gay writer's group that met briefly from 1980—1981. The Violet Quill included other prolific gay writers like Andrew Holleran and Felice Picano.

An earlier novel Nocturnes for the King of Naples (1978) and a later novel The Married Man (2000) are also gay-themed and draw heavily on White's own life. In 2006 he published a nonfiction autobiography entitled My Lives. It is unusual in that it is organized by theme, rather than chronologically. White's autobiographical works are frank and unapologetic about his promiscuity and his HIV-positive status. In 1982, White helped found the Gay Men's Health Crisis, in New York City.. In Paris, in 1984, he was closely involved in the foundation of the French HIV/AIDS NGO AIDES.

White has explained: "Writing has always been my recourse when I've tried to make sense of my experience or when it's been very painful. When I was 15 years old, I wrote my first (unpublished) novel about being gay, at a time when there were no other gay novels. So I was really inventing a genre, and it was a way of administering a therapy to myself, I suppose."

Though he is openly gay himself, not all of his works centre on gay themes. His debut Forgetting Elena (1973) is set on an imaginary island. The novel can be read as commenting on gay culture, but only in a highly coded and indirect manner. Caracole (1985) centers on heterosexual characters, relationships, and desires. Fanny: A Fiction (2003) is a historical novel about Frances Trollope and Frances Wright. White's 2006 play Terre Haute (produced in New York City in 2009) portrays discussions that take place when a prisoner based on Timothy McVeigh is visited by a writer based on Gore Vidal. (In real life McVeigh and Vidal corresponded but did not meet.)

White has been influential as a literary and cultural critic, particularly on gay issues. He has received many awards and distinctions; among these, he is a Member of the American Academy of Arts and Letters, an Officier de l'Ordre des Arts et des Lettres, and a Member of the American Academy of Arts and Sciences.