Orlovsky was born in the Lower East Side of New York City, the son of Katherine (née Schwarten) and Oleg Orlovsky, a Russian immigrant. He was raised in poverty and was forced to drop out of Newtown High School in his senior year so he could support his impoverished family. After many odd jobs, he began working as an orderly at Creedmoor State Mental Hospital, known today as Creedmoor Psychiatric Center.

In 1953 Orlovsky was drafted into the Army for the Korean War, he was 19 years old. Army psychiatrists ordered his transfer off the front to work as a medic in a San Francisco hospital.

He met Ginsberg while working as a model for the painter Robert La Vigne in San Francisco in December 1954. Prior to meeting Ginsberg, Orlovsky had made no deliberate attempts at becoming a poet. With Ginsberg's encouragement, Orlovsky began writing in 1957 while the pair were living in Paris. Accompanied by other beat writers, Orlovsky traveled extensively for several years throughout the Middle East, Northern Africa, India, and Europe. Orlovsky was Ginsberg's lover in an open relationship for three decades, which ended in 1987 and they remained close friends and even roommates until Ginsberg's death in 1997.

In 1974, Orlovsky joined the faculty of the Jack Kerouac School of Disembodied Poetics at the Naropa Institute in Boulder, Colorado, teaching poetry. In 1979 he received a $10,000 grant from the National Endowment for the Arts to continue his creative endeavors.

In May 2010, friends reported that Orlovsky, who had been battling lung cancer for several months, was moved from his home in St. Johnsbury, Vermont to the Vermont Respite House in Williston. He died there on May 30, 2010, age 76.

• Dear Allen, Ship will land Jan 23, 58 (1971)
• Lepers Cry (1972)
• Clean Asshole Poems & Smiling Vegetable Songs (1978) (reprinted 1992)
• Straight Hearts' Delight: Love Poems and Selected Letters (with Allen Ginsberg) (1980)
• Dick Tracy's Gelber Hut (German translation) (1980)

His work has also appeared in The New American Poetry 1945—1960 (1960), The Beatitude Anthology (1965), as well as the literary magazines Yugen and Outsider. Orlovsky appeared in three films: Andy Warhol's Couch (1965) and in two films by photographer Robert Frank, Me and My Brother (1969) (a film documenting his brother Julius Orlovsky's mental illness) and One Hour (C'est Vrai) (a 60 minute one-take video made for French television in 1992).