Miller was brought up in Brooklyn, and he wrote about his childhood experiences there in Black Spring (1936). In 1924 he left his job with Western Union in New York to devote himself to writing. In 1930 he went to France. Tropic of Cancer (published in France in 1934, in the United States in 1961) is based on his hand-to-mouth existence in Depression-ridden Paris. Tropic of Capricorn (France, 1939; U.S., 1961) draws on the earlier New York phase.

Miller's visit to Greece in 1939 inspired The Colossus of Maroussi (1941), a meditation on the significance of that country. In 1940–41 he toured the United States extensively and wrote a sharply critical account of it, The Air-Conditioned Nightmare (1945), which dwelt on the cost in human terms of mechanization and commercialization.

After settling in Big Sur on the California coast, Miller became the centre of a colony of admirers. Many of them were writers of the Beat generation who saw parallels to their own beliefs in Miller's whole-hearted acceptance of the degrading along with the sublime. At Big Sur, Miller produced his Rosy Crucifixion trilogy, made up of Sexus, Plexus, and Nexus (U.S. edition published as a whole in 1965). It covers much the same period of Miller's life as Tropic of Capricorn and, together with that book, traces the stages by which the hero-narrator becomes a writer. The publication of the “Tropics” in the United States provoked a series of obscenity trials that culminated in 1964 in a Supreme Court decision rejecting state court findings that the book was obscene.

Other important books by Miller are the collections of essays The Cosmological Eye (1939) and The Wisdom of the Heart (1941). He was also a watercolourist; he exhibited internationally and wrote about art in To Paint Is To Love Again (1960). Various volumes of his correspondence have been published: with Lawrence Durrell (1963), to Anaïs Nin (1965), and with Wallace Fowlie (1975).