Ken Kesey was born in La Junta, Colorado to dairy farmers Frederick A. Kesey and Geneva Smith. In 1946, the family moved to Springfield, Oregon. A champion wrestler in both high school and college, he graduated from Springfield High School in 1953.

In 1956, while attending college at the University of Oregon in neighboring Eugene, Kesey eloped with his high-school sweetheart, Norma "Faye" Haxby, whom he had met in seventh grade. They had three children, Jed, Zane, and Shannon; Kesey had another child, Sunshine, in 1966 with fellow Merry Prankster Carolyn Adams.

Kesey attended the University of Oregon's School of Journalism, where he received a degree in speech and communication in 1957, where he was also a brother of Beta Theta Pi. He was awarded a Woodrow Wilson National Fellowship in 1958 to enroll in the creative writing program at Stanford University, which he did the following year. While at Stanford, he studied under Wallace Stegner and began the manuscript that would become One Flew Over the Cuckoo's Nest.

At Stanford in 1959, Kesey volunteered to take part in a CIA-financed study named Project MKULTRA at the Menlo Park Veterans Hospital. The project studied the effects of psychoactive drugs, particularly LSD, psilocybin, mescaline, cocaine, AMT, and DMT on people. Kesey wrote many detailed accounts of his experiences with these drugs, both during the Project MKULTRA study and in the years of private experimentation that followed. Kesey's role as a medical guinea pig, as well as his stint working at a state veterans' hospital, inspired him to write One Flew Over the Cuckoo's Nest in 1962. The success of this book, as well as the sale of his residence at Stanford, allowed him to move to La Honda, California, in the mountains south of San Francisco. He frequently entertained friends and many others with parties he called "Acid Tests" involving music (such as Kesey's favorite band, The Warlocks, later known as the Grateful Dead), black lights, fluorescent paint, strobes and other "psychedelic" effects, and, of course, LSD. These parties were noted in some of Allen Ginsberg's poems and are also described in Tom Wolfe's The Electric Kool-Aid Acid Test, as well as The Strange and Terrible Saga of the Outlaw Motorcycle Gangs by Hunter S. Thompson and Freewheelin Frank, Secretary of the Hell's Angels by Frank Reynolds.

In 1959, Kesey wrote Zoo, a novel about the beatniks living in the North Beach community of San Francisco, but it was never published. In 1960, he wrote End of Autumn, about a young man who leaves his working class family after he gets a scholarship to an Ivy League school, also unpublished.

The inspiration for One Flew Over the Cuckoo's Nest came while working on the night shift (with Gordon Lish) at the Menlo Park Veterans' Hospital. There, Kesey often spent time talking to the patients, sometimes under the influence of the hallucinogenic drugs with which he had volunteered to experiment. Kesey did not believe that these patients were insane, rather that society had pushed them out because they did not fit the conventional ideas of how people were supposed to act and behave. Published in 1962, it was an immediate success; in 1963, it was adapted into a successful stage play by Dale Wasserman; in 1975, Milo? Forman directed a screen adaptation, which won the "Big Five" Academy Awards: Best Picture, Best Actor (Jack Nicholson), Best Actress (Louise Fletcher), Best Director (Forman) and Best Adapted Screenplay (Lawrence Hauben, Bo Goldman).

Kesey was originally involved in creating the film, but left two weeks into production. He claimed never to have seen the movie because of a dispute over the $20,000 he was initially paid for the film rights. Kesey loathed the fact that, unlike the book, the film was not narrated by the Chief Bromden character, and he disagreed with Jack Nicholson being cast as Randle McMurphy (he wanted Gene Hackman). Despite this, Faye Kesey has stated that Ken was generally supportive of the film and pleased that it was made.

When the publication of his second novel, Sometimes a Great Notion in 1964 required his presence in New York, Kesey, Neal Cassady, and others in a group of friends they called the "Merry Pranksters" took a cross-country trip in a school bus nicknamed "Furthur". NMAH | Signboard, Pass the Acid Test This trip, described in Tom Wolfe's The Electric Kool-Aid Acid Test (and later in Kesey's own screenplay "The Further Inquiry") was the group's attempt to create art out of everyday life. In New York, Cassady introduced Kesey to Jack Kerouac and Allen Ginsberg, who then turned them on to Timothy Leary. Sometimes a Great Notion was made into a 1971 film starring and directed by Paul Newman; it was nominated for two Academy Awards, and in 1972 was the first film shown by the new television network HBO, in Wilkes-Barre, Pennsylvania.

Kesey was arrested for possession of marijuana in 1965. In an attempt to mislead police, he faked suicide by having friends leave his truck on a cliffside road near Eureka, along with an elaborate suicide note, written by the pranksters. Kesey fled to Mexico in the back of a friend's car. When he returned to the United States eight months later, Kesey was arrested and sent to the San Mateo County jail in Redwood City, California, for five months. On his release, he moved back to the family farm in Pleasant Hill, Oregon, in the Willamette Valley, where he spent the rest of his life. He wrote many articles, books (mostly collections of his articles), and short stories during that time.

In 1994 he toured with members of the Merry Pranksters performing a musical play he wrote about the millennium called Twister: A Ritual Reality. Many old and new friends and family showed up to support the Pranksters on this tour that took them from Seattle's Bumbershoot, all along the West Coast including a sold out two-night run at The Fillmore in San Francisco to Boulder, Colorado, where they coaxed (or pranked) the Beat Generation poet Allen Ginsberg into performing with them. Kesey, always a friend to musicians since his days of the Acid Test, enlisted the band Jambay, one of the original bands of the jam band genre, to be his "pit orchestra." Jambay played an acoustic set before each Twister performance and an electric set after each show.

Kesey mainly kept to his home life in Pleasant Hill, preferring to make artistic contributions on the Internet, or holding ritualistic revivals in the spirit of the Acid Test. He occasionally made appearances at rock concerts and festivals, bringing the second bus and various Pranksters with him. In the official Grateful Dead DVD release The Closing of Winterland (2003), which documents the monumental New Year's '78 concert, Kesey is featured in a between-set interview. More notably, he appeared at the Hog Farm Family Pig-Nic Festival (organized by Woodstock MC Wavy Gravy, in Laytonville, California), where they mock-canonized a very ill but still quite aware Dr. Timothy Leary atop "Furthur". He also performed on stage with Jambay at the Pig-Nic, playing a few songs from Twister with members of the original cast.

In 1984, Kesey's son Jed, a wrestler for the University of Oregon, was killed on the way to a wrestling tournament when the team's bald-tired van crashed. This deeply affected Kesey, who later said Jed was a victim of conservative, anti-government policy that starved the team of proper funding. There is a memorial dedicated to Jed on the top of Mount Pisgah, which is near the Keseys' home in Pleasant Hill. At a Grateful Dead Halloween concert just days after promoter Bill Graham died in a helicopter crash, Kesey appeared on stage in a tuxedo and delivered a eulogy while the Grateful Dead was playing the song Dark Star, and he mentioned that Graham had paid for Jed's mountain-top memorial.

On August 14, 1997, Kesey and his Pranksters attended a Phish concert in Darien Lake, New York. After making a somewhat mystical appearance in the parking lot before the show, Kesey and the Pranksters appeared onstage with the band and performed a dance-trance-jam session involving several characters from The Wizard of Oz and Frankenstein. Kesey kept asking, "Where have all the Bozos gone? To the Phish concert, and the Further Festival." Trey Anastasio was quoted as the Pranksters exited, "That's what happens when you do too much acid 30 years later." The band then performed the song "Camel Walk", with a groove that has become known as the "Pranksters Jam".

In June 2001, Kesey was invited and accepted as the keynote speaker at the annual commencement of The Evergreen State College.

His last major work was an essay for Rolling Stone magazine calling for peace in the aftermath of the September 11, 2001 attacks.

In 1997, health problems began to take their toll on Kesey, starting with a stroke that year. Then soon after his stroke he was diagnosed with diabetes. On October 25, 2001 Kesey had surgery on his liver to remove a tumor. He never recovered from the operation and died of complications on November 10, 2001, aged 66.

Some of Kesey's better-known works include:

• One Flew Over the Cuckoo's Nest (1962, novel)
• Volume Five (1963, magazine article)
• Sometimes a Great Notion (1964, novel)
• Kesey's Garage Sale (1973, collection of essays)
• Demon Box (1986, collection of essays and short stories)
• Caverns (1989, novel)
• The Further Inquiry (1990, play)
• Sailor Song (1992, novel)
• Last Go Round (1994, novel, written with Ken Babbs)
• Twister (1994, play)
• Kesey's Jail Journal (2003, collection of essays)