From this experience, and his experience as a psychiatric aide working the night-shift in the same Menlo Park hospital, Kesey wrote his most celebrated novel, One Flew Over The Cuckoo's Nest, during which he began his own experimentations with psychedelic drugs. Kesey often spent time talking to the patients, sometimes under the influence of the hallucinogenic drugs with which he had volunteered to experiment. He believed that these patients were not insane, but that society had pushed them out because they did not fit the conventional ideas of how people were supposed to act and behave. One Flew Over The Cuckoo’s Nest was told from the hallucinatory point of view of a Columbian Indian patient, Chief Broom, and it was the film version's neglect of that character which later caused Kesey to sue, unsuccessfully, to prevent the film's release.

After this novel was published, Kesey purchased property in La Honda, California where he and the Merry Pranksters (including Neal Cassady, the inspiration for Jack Kerouc’s Dean Moriarty in ‘On the Road’) threw the now famous Acid Test parties during the mid 60s. The events, fueled by diverse and intriguing guests, day-glo decorations in the trees, music from hidden speakers, and plenty of LSD, are now well documented. In 1964, Kesey and the Merry Pranksters set out on their cross-country bus trip to the East coast in a psychedelically painted school bus named Furthur. Along the way they met, among others, Allen Ginsberg,  Timothy Leary, and Jack Kerouac. The trip has been immortalized by Tom Wolfe's book 'The Electric Kool-Aid Acid Test'.