Orlovsky was born to Russian parents Oleg and Katharina Orlovsky in the Lower East Side of New York City . Orlovsky was raised in poverty and was forced to drop out of 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.
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.
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.