Born in Greenfield, Massachusetts and reared in Chicago, Herbert Huncke was a street hustler, high school dropout and drug user. Huncke's life was centered around living as a hobo, jumping trains across the vast expanse of the United States, bonding through a shared destitution and camaraderie with other vagrants. Although Huncke later came to regret his loss of family ties, in his autobiography, Guilty of Everything, he states that his lengthy jail sentences were a partial result of his lack of family support. Huncke left Chicago as a teenager after his parents divorced. Despite the fantasies the largely college-educated Beat Generation had about Huncke, he was from as much of a middle-class background as they were.

Huncke hitchhiked to New York City in 1939. He was dropped off at 103rd and Broadway, and he asked the driver how to find 42nd Street. "You walk straight down Broadway," the man said, "and you will find 42nd Street." Huncke, always a stylish dresser, bought a boutonnière for his jacket and headed for 42nd Street. For the next 10 years, Huncke was a 42nd Street regular and became known as the "Mayor of 42nd Street."

At this point, Huncke's regular haunts were 42nd Street and Times Square, where he associated with a variety of people, including prostitutes (both male and female) and sailors. During World War II, Huncke shipped out to sea as a United States Merchant Marine to ports in South America, Africa and Europe. He landed on the beach of Normandy three days after the invasion.

Aboard ships, Huncke would overcome his drug addiction or maintain it with morphine syrettes supplied by the ship medic. When he returned to New York, he returned to 42nd Street, and it was after one such trip where he met the then-unknown William S. Burroughs, who was selling a sub-machine gun and a box of syrettes. Their first meeting was not cordial: from Burroughs' appearance and manner, Huncke suspected that he was "heat" (undercover police or FBI). Assured that Burroughs was harmless, Huncke bought the morphine and, at Burroughs' request, immediately gave him an injection. Burroughs later wrote a fictionalized account of the meeting in his first novel, Junkie. Huncke also became a close friend of Joan Adams Vollmer Burroughs, William's common-law wife, sharing with her a taste for amphetamines. In the late 1940s he was invited to Texas to grow marijuana on the Burroughs farm.

During the late 1940s, Huncke was recruited to be a subject in Alfred Kinsey's research on the sexual habits of the American male. He was interviewed by Kinsey, and recruited fellow addicts and friends to participate. Huncke was a writer, unpublished, since his days in Chicago and gravitated toward literary types and musicians. In the music world, Huncke visited all the jazz clubs and associated with Billie Holiday, Charlie Parker and Dexter Gordon (with whom he was once busted on 42nd Street for breaking into a parked car). When he first met Allen Ginsberg, Jack Kerouac and William Burroughs, they were interested in writing and also unpublished. They were inspired by his stories of 42nd Street life, criminal life, street slang and Huncke's vast experience with drugs. Huncke was immortalized in Kerouac's "On the Road" as the character Elmer Hassel.

Although it was his passion for thievery, heroin use and the outlaw lifestyle which fueled his daily activities, ultimately, when he was caught, he never informed on his friends. In the late 1940s, Allen Ginsberg, Jack Melody and "Detroit Redhead" flipped a car in Queens, New York, while trying to run down a motorcycle cop. Although Huncke was not at the scene of the crime he was arrested in Manhattan, because he resided with Ginsberg, and Huncke received a heavy prison sentence.

"Someone had to do the bit," Huncke said years later.

Huncke himself was a natural storyteller, a unique character with a paradoxically honest take on life. Later, after the formation of the so-called Beat Generation, members of the Beats encouraged Huncke to publish his notebook writings, which he did with limited success in 1964 with Diane DiPrima's Poet's Press. (Huncke's Journal) Huncke used the word "Beat" to describe someone living with no money and few prospects. "Beat to my socks," he said. Huncke coined the phrase in a conversation with Jack Kerouac, who was interested in how their generation would be remembered. "I'm beat," was Huncke's reply, meaning tired and beat to his socks. Kerouac used the term to describe an entire generation. Jack Kerouac later insisted that "Beat" was derived from beatification, to be supremely happy. However, it is thought that this definition was a defense of the beat way of life, which was frowned upon and offended many American sensibilities.

His autobiography, titled Guilty of Everything, was lived in the 1940s and 1960s but published in the 1990s.

Huncke died in 1996 at age 81. He had been living for several years in a garden apartment on East 7th Street near Avenue D in New York City, supported fiancially by his friends David Sands, Jerome Poynton, Tim Moran, Gani Remorca, Raymond Foye and many others. In his last few years, he lived in the Chelsea Hotel, where his rent came from financial support from Jerry Garcia of The Grateful Dead, whom Huncke never met.

Jack Kerouac described Huncke in his "Now it's Jazz" reading from Desolation Angels, chapter 77:

Huck, whom you'll see on Times Square, somnolent and alert, sad, sweet, dark, holy. Just out of jail. Martyred. Tortured by sidewalks, starved for sex and companionship, open to anything, ready to introduce a new world with a shrug.

John Clellon Holmes described Albert Ancke, his representation of Huncke in Go in Chapter 14 of part 2:

A sallow, wrinkled little hustler, hatless and occupying a crumpled sport shirt as though crouched in it to hide his withered body.

Admired by David Wojnarowicz in his personal diaries, In the Shadow of the American Dream, where their meetings/dates are documented.

Frank McCourt mentions knowing Huncke in Chapter 16 of Teacher Man:

"Alcohol is not his habit but he'll kindly allow you to buy him a drink at Montero's. His voice is deep, gentle and musical. He never forgets his manners and you'd rarely think of him as Huncke the Junkie. He respects law and obeys none of it."

Huncke was featured in several documentaries about the Beat generation, including Janet Forman's "The Beat Generation: An American Dream," Richard Lerner and Lewis MacAdams' "What Happened to Kerouac?" and John Antonelli's "Kerouac, the Movie." He also starred in his only acting role in James Rasin and Jerome Poynton's "The Burning Ghat."