He was born in New York City and grew up in Glendale, California. At a young age he was diagnosed with Cystic Fibrosis, a condition which would influence his art and ultimately claim his life. He studied literature at California State University, Long Beach and the University of California, Irvine. He moved to Los Angeles in 1976. In 1978, he published his first book, The Kid Is A Man. He also worked with the improv comedy group The Groundlings.
He was the subject of the documentary SICK: The Life & Death of Bob Flanagan, Supermasochist (1997) a film by Kirby Dick, which films the final years of Bob's life.
Flanagan is featured in the widely banned music video for the song "Happiness in Slavery" by Nine Inch Nails. In the video, he plays a character who worships a machine. He offers a candle to an altar, before ceremonially undressing and washing. The slave (Bob) then lies down on an intelligent torture machine that molests and ultimately kills him, all with a mixture of pain and pleasure on his face.
In 1993 he also appeared in the video for the Danzig song "It's Coming Down". In the uncensored version of the video, Flanagan hammers a nail through the head of his penis before urinating on the lens of the camera recording him.
While some of his performances were notable for acts of extreme masochism (on at least one occasion he hammered a nail through his penis, while cracking jokes), he also wrote rather clever, humorous songs, many of them intended as much for children as adults.