Born in Salt Lake City and raised by an alcoholic father in Denver, Cassady spent much of his youth bouncing between skid-row hotels with his father and in reform schools for car theft. In 1946 Cassady met Jack Kerouac and Allen Ginsberg at Columbia University in New York and quickly became friends with them and the circle of artists and writers there. He took Ginsberg as a lover for a short time and traveled cross-country with Kerouac later. Cassady proved to be the catalyst for the Beat Movement, appearing as the hero Dean Moriarity in Kerouac's On The Road; Ginsberg mentioned him as well, in his ground-breaking poem, Howl ("N.C., secret hero of these poems...").
In the late 1950's, Cassady settled down, married Carolyn Cassady, and went to work for the railroad. While he kept in touch with his Beat counterparts, they drifted apart philosophically. In 1964, Cassady met up with Ken Kesey and Tom Wolf, becoming part of the Merry Pranksters and serving as the crazed driver of the bus named Furthur which was immortalized in Wolf's novel, The Electric Kool-Aid Acid Test. He later played a prominent role in the California psychedelic scene of the 1960s.
After a party in Mexico in 1968 he went walking by a railroad track to reach the next town, but passed out in the cold and rainy night wearing nothing but a T-shirt and his jeans. In the morning he was found in a coma by the track and brought to the closest hospital, where he died a few hours later. Kesey retells the story of his death in a short story where Cassady is quoted with mumbling the number of nails in the rail he'd counted so far, as his last words before dying.
Cassady never earned anything for his role in the Beat Movement, but his autobiography The First Third was published posthumonously.