In 1943 while living in New York City, he befriended Allen Ginsberg and Jack Kerouac, the mutually influential foundation of which grew into the Beat Generation, and later the 1960s counterculture.
In 1948 Burroughs was arrested after police searched his home and found letters between him and Allen Ginsberg referring to a possible delivery of marijuana.
After leaving Mexico, Burroughs drifted through South America for several months, looking for a drug called yagé, which promised the user telepathy. A book composed of letters between Burroughs and Ginsberg, The Yage Letters, was published in 1963 by City Lights Books.
Before Vollmer died, Burroughs had largely completed his first two novels in Mexico, although Queer was not published until 1985. Junkie was written at the urging of Allen Ginsberg, who was instrumental in getting the work published, even as a cheap mass-market paperback.
During 1953, Burroughs was at loose ends. Due to legal problems, he was unable to live in the cities towards which he was most inclined. He spent time with his parents in Palm Beach, Florida, and New York City with Allen Ginsberg. When Ginsberg refused his romantic advances, Burroughs went to Rome to meet Alan Ansen on a vacation financed from his parents' continuing support.
He left for Tangier in November 1954 and spent the next four years there working on the fiction that would later become Naked Lunch, as well as attempting to write commercial articles about Tangier. He sent these writings to Ginsberg, his literary agent for Junkie, but none were published until 1989 when Interzone, a collection of short stories, was published. Under the strong influence of a marijuana confection known as majoun and a German-made opioid called Eukodol, Burroughs settled in to write. Eventually, Ginsberg and Kerouac, who had traveled to Tangier in 1957, helped Burroughs type, edit, and arrange these episodes into Naked Lunch.
Excerpts from Naked Lunch were first published in the United States in 1958. The novel was initially rejected by City Lights Books, the publisher of Ginsberg's Howl; and Olympia Press publisher Maurice Girodias, who had published English-language novels in France that were controversial for their subjective views of sex and anti-social characters. But Allen Ginsberg worked to get excerpts published in Black Mountain Review and Chicago Review in 1958.
Burroughs moved into a rundown hotel in the Latin Quarter of Paris in 1959 when Naked Lunch was still looking for a publisher. Tangier, with its easy access to drugs, small groups of homosexuals, growing political unrest, and odd collection of criminals, had become increasingly unhealthy for Burroughs. He went to Paris to meet Ginsberg and talk with Olympia Press. In so doing, he left a brewing legal problem, which eventually transferred itself to Paris. Paul Lund, a British former career criminal and cigarette smuggler whom Burroughs met in Tangier, was arrested on suspicion of importing narcotics into France. Lund gave up Burroughs, and some evidence implicated Burroughs in the possible importation of narcotics into France. Once again, the man faced criminal charges, this time in Paris for conspiracy to import opiates, when the Moroccan authorities forwarded their investigation to French officials. Yet it was under this impending threat of criminal sanction that Maurice Girodias published Naked Lunch; the publication helped in getting Burroughs a suspended sentence, since a literary career, according to Ted Morgan, is a respected profession in France.
Burroughs left Paris for London in 1966 to take the cure again with Dr. Dent, a well-known English medical doctor who spearheaded a reputedly painless heroin withdrawal treatment using the drug apomorphine.
In 1974, concerned about his friend's well-being, Allen Ginsberg gained for Burroughs a contract to teach creative writing at the City College of New York. Burroughs successfully withdrew from heroin use and moved to New York.
In 1976, Billy Burroughs was eating dinner with his father and Allen Ginsberg in Boulder, Colorado, at Ginsberg’s Buddhist poetry school (Jack Kerouac School of Disembodied Poetics) at Chogyam Trungpa's Naropa University when he began to vomit blood. Burroughs senior had not seen his son for over a year and was alarmed at his appearance when Billy arrived at Ginsberg’s apartment. Although Billy had successfully published two short novels in the 1970s, and was deemed by literary critics like Ann Charters as a bona fide "second generation beat writer", his brief marriage to a teenage waitress had disintegrated. Under his constant drinking, there were long periods where Billy was out of contact with any of his family or friends. The diagnosis was liver cirrhosis so complete that the only treatment was a rarely performed liver transplant operation. Fortunately, the University of Colorado Medical Center was one of two places in the nation that performed transplants under the pioneering work of Dr. Thomas Starzl. Billy underwent the procedure and beat the thirty-percent survival odds. His father spent many months in 1976 and 1977 in Colorado, helping Billy through many additional surgeries and complications. Ted Morgan’s biography asserts that their relationship was not spontaneous and lacked real warmth or intimacy. Allen Ginsberg was supportive to both Burroughs and his son throughout the long period of recovery.
In 1981, Billy Burroughs died in Florida. He had cut off contact with his father several years before, even publishing an article in Esquire magazine claiming the author had poisoned his life and revealing that he had been molested by one of his father's friends as a fourteen-year-old while visiting his father in Tangier, something that he had previously kept to himself. The liver transplant had not cured his urge to drink, and Billy suffered from serious health complications years after the operation. He had stopped taking his transplant rejection drugs and was found near the side of a Florida highway by a stranger. He died shortly afterwards. Burroughs was in New York when he heard from Allen Ginsberg of Billy's death.
He was finally inducted into the American Academy and Institute of Arts and Letters in 1983 after several attempts by Allen Ginsberg to get him accepted.