Kesey was born in La Junta, Colorado, to dairy farmers Geneva (née Smith) and Frederick A. Kesey. In 1946, the family moved to Springfield, Oregon. Kesey was a champion wrestler in high school and college in the 174-pound weight division. He almost qualified to be on the Olympic team, but a serious shoulder injury stopped his wrestling career. He graduated from Springfield High School in 1953. An avid reader and filmgoer, the young Kesey took John Wayne, Edgar Rice Burroughs, and Zane Grey as his role models (later naming a son Zane) and toyed with magic, ventriloquism, and hypnotism.

In 1956, while attending the University of Oregon School of Journalism and Communication in neighboring Eugene, Oregon, Kesey eloped with his high-school sweetheart, Oregon State College student Norma “Faye” Haxby, whom he had met in seventh grade. According to Kesey, “Without Faye, I would have been swept overboard by notoriety and weird, dope-fueled ideas and flower-child girls with beamy eyes and bulbous breasts.” Married until his death at the age of 66, they had three children: Jed, Zane, and Shannon. Additionally, with the approval of Faye Kesey, Ken fathered a daughter, Sunshine Kesey, with fellow Merry Prankster Carolyn “Mountain Girl” Adams. Born in 1966, Sunshine was raised by Adams and her stepfather, Jerry Garcia.

Kesey had a football scholarship for his first year, but switched to the University of Oregon wrestling team as a better fit for his build. After posting a .885 winning percentage in the 1956–57 season, he received the Fred Low Scholarship for outstanding Northwest wrestler. In 1957, Kesey was second in his weight class at the Pacific Coast intercollegiate competition. He remains “ranked in the top 10 of Oregon Wrestling’s all time winning percentage.”

A member of Beta Theta Pi throughout his studies, Kesey graduated from the University of Oregon with a B.A. in speech and communication in 1957. Increasingly disengaged by the playwriting and screenwriting courses that comprised much of his major, he began to take literature classes in the second half of his collegiate career with James B. Hall, a cosmopolitan alumnus of the Iowa Writers’ Workshop who had previously taught at Cornell University and later served as provost of College V at the University of California, Santa Cruz. Hall took on Kesey as his protege and cultivated his interest in literary fiction, introducing Kesey (whose reading interests were hitherto confined to science fiction) to the works of Ernest Hemingway and other paragons of literary modernism. After the last of several brief summer sojourns as a struggling actor in Los Angeles, he published his first short story (“First Sunday of September”) in the Northwest Review and successfully applied to the highly selective Woodrow Wilson National Fellowship for the 1958–59 academic year.

While still enrolled at the University of Oregon in 1957, Kesey wrote End of Autumn; according to Rick Dogson, the novel “focused on the exploitation of college athletes by telling the tale of a football lineman who was having second thoughts about the game.” Although Kesey came to regard the unpublished work as juvenilia, an excerpt served as his Stanford Creative Writing Center application sample.

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 he had volunteered to experiment with. Kesey did not believe that these patients were insane, but 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 under the guidance of Cowley in 1962, the novel was an immediate success; in 1963, it was adapted into a successful stage play by Dale Wasserman, and in 1975, Miloš 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 and Bo Goldman).

Kesey’s role as a medical guinea pig, as well as his stint working at the Veterans’ Administration hospital, inspired him to write One Flew Over the Cuckoo’s Nest. The success of this book, as well as the demolition of the Perry Lane cabins in August 1963, allowed him to move to a log house at 7940 La Honda Road in La Honda, California, a rustic hamlet in the Santa Cruz Mountains fifteen miles to the west of the Stanford University campus. He frequently entertained friends and many others with parties he called “Acid Tests,” involving music (including the Stanford-educated Anonymous Artists of America and Kesey’s favorite band, the Grateful Dead), black lights, fluorescent paint, strobe lights, LSD, and other psychedelic effects. These parties were described in some of Allen Ginsberg’s poems and served as the basis for Tom Wolfe’s The Electric Kool-Aid Acid Test, an early exemplar of the nonfiction novel. Other firsthand accounts of the Acid Tests appear in Hell’s Angels: The Strange and Terrible Saga of the Outlaw Motorcycle Gangs by Hunter S. Thompson and the 1967 Hells Angels memoir Freewheelin Frank:, Secretary of the Angels (Frank Reynolds; ghostwritten by Michael McClure).

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. This trip, described in Tom Wolfe’s The Electric Kool-Aid Acid Test (and later in Kesey’s unproduced screenplay, The Furthur Inquiry) was the group’s attempt to create art out of everyday life, and to experience roadway America while high on LSD. In an interview after arriving in New York, Kesey is quoted as saying, “The sense of communication in this country has damn near atrophied. But we found as we went along it got easier to make contact with people. If people could just understand it is possible to be different without being a threat.” A huge amount of footage was filmed on 16 mm cameras during the trip, which remained largely unseen until the release of Alex Gibney and Alison Elwood’s film Magic Trip in 2011.

Kesey was arrested in La Honda, California, 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. He returned to the United States eight months later. On January 17, 1966, Kesey was sentenced to six months to be served at the San Mateo County jail in Redwood City, California. Two nights later, he was arrested again, this time with Carolyn Adams, while smoking marijuana on the rooftop of Stewart Brand’s Telegraph Hill home in San Francisco. 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.

After the bus trip, the Pranksters threw parties they called Acid Tests around the San Francisco Bay Area from 1965 to 1966. Many of the Pranksters lived at Kesey’s residence in La Honda. In New York, Cassady introduced Kesey to Jack Kerouac and Allen Ginsberg, who then turned them on to Timothy Leary. Sometimes a Great Notion inspired a 1970 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.

In 1984, Kesey’s 20-year-old son Jed, a wrestler for the University of Oregon, suffered severe head injuries on the way to a tournament when the team’s van crashed after sliding off the highway. Two days later, he was declared brain dead and his parents gave permission for his organs to be donated.

Kesey was diagnosed with diabetes in 1992. 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, which 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 the Beat Generation poet Allen Ginsberg into performing with them.

On August 14, 1997, Kesey and his Pranksters attended a Phish concert in Darien Lake, New York. 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.

In 1997, health problems began to weaken Kesey, starting with a stroke that year. On October 25, 2001, Kesey had surgery on his liver to remove a tumor. He did not recover from that operation and died of complications on November 10, 2001, at age 66.

Reflecting upon this period in a 1999 interview with Robert K. Elder, Kesey recalled, “I was too young to be a beatnik, and too old to be a hippie.”

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 attacks.