One Flew Over The Cuckoo's Nest is a novel set in an Oregon mental institution in the late 1950s or early 1960s. The novel is narrated by "Chief" Bromden, a very large, Native American man who is believed to be deaf and dumb, and has been a patient at the hospital for a number of years.

     In the opening of Part I, Chief Bromden is describing the staff who work at the asylum, including the African American orderlies, who he believes commit secret sexual acts, and Nurse Ratched, who he refers to as Big Nurse. Chief Bromden uses mechanical imagery to describe the orderlies, Nurse Ratched, and other mechanisms of power, and collectively refers to them as "the Combine". Chief Bromden describes being sedated for any kind of disobedience, like refusing to be shaved, and refers to his sedated state as being in a fog.

     The patients are divided into two groups: Acutes and Chronics. Acutes are patients who seem to have a hope of one day being released, while Chronics are in the hospital for life, because there is no place for them in society.

     Believed to be incapable of hearing or speaking, Chief Bromden is able to overhear conversations and observe interactions that the staff would not want other patients to witness, and he therefore has more insight about the true workings of the ward.

     One morning, a man named Randle P. McMurphy is admitted to the ward as a transfer from a work farm. McMurphy is a big, red-headed, wisecracking man with a scar on his face, and he immediately stands out to Chief Bromden and the rest of the patients because of his loud, boisterous personality.

     Chief Bromden's narration is not in a strictly linear style, and shortly after the introduction of McMurphy the Chief relates what a typical day is like on the ward, which Nurse Ratched keeps in eerily mechanical working order, and mixes this with remembrances from his early life, drawing parallels between the mechanisms of power both inside the hospital and outside.

     On McMurphy's first day on the ward, the Acute patients have their daily group meeting with Nurse Ratched and Dr. Spivey, where the patients engage as part of a Therapeutic Community. This is done under the claims of being key to healing their mental states, but is actually one of Nurse Ratched's methods of controlling the patients, by forcing them to confess their sins to the group. In this particular meeting, the discussion is focused on an Acute patient named Harding, and his relationship with his wife. After this meeting, McMurphy confronts the group and tries to convince them that this not for their mental well-being, but to keep them weak by having them constantly pick at each other's flaws. In discussion about the Nurse's control over them, the other patients explain to McMurphy that they are kept in line by threat of being sent to the disturbed ward, or the "Shock Shop", where electro shock therapy is administered. After this discussion, McMurphy makes a bet with Harding and the other Acutes that he can get the best of Nurse Ratched without doing anything that actually violates her rules.

     Later that evening, McMurphy plays cards with some of the Acutes, and Chief Bromden observes his control throughout the game. When evening medications are administered, the evening nurse is flustered by McMurphy, and ends up dropping Chief Bromden's red pill. In the dormitory, McMurphy warns the Chief that Geever is coming, prompting the Chief to quickly feign his medication has taken effect, prompting McMurphy to later remark that Chief Bromden is obviously not deaf.

     The first night in a long time that Chief Bromden hasn't had his red pill, he has dream visions of a mechanical hell in which patients are tortured and Old Blastic is killed. When the Chief is awoken by the night aide Mr. Turkle, telling him he's having a bad dream, the Chief sees that Blastic has indeed died.

     The next morning Chief Bromden and the other patients awake to the sounds of McMurphy singing loudly in the latrine. He saunters around the hallway wearing only a towel wrapped around his waist, and is in the midst of asking one of the aides for some toothpaste when Nurse Ratched arrives. Visibly incensed to see a nearly naked McMurphy parading in the hallway, Nurse Ratched loses her temper with Williams and Washington for failing to provide McMurphy with a proper uniform.

     That afternoon, McMurphy is irritated during a game of cards by the constant music being played. When he broaches the concern to Nurse Ratched, she dismisses him as selfishly wanting to deny the Chronic patients their music, and ignores his idea to have a games table set up in a separate room. McMurphy then circumvents Nurse Ratched and has an informal meeting with Dr. Spivey, where he brings up the concern and makes Dr. Spivey think that moving the games table to a separate room was his idea. When Dr. Spivey presents the idea during group meeting, Nurse Ratched again appears to have been bested by McMurphy.

     A few days into McMurphy's stay on the ward, he brings up the topic of watching the upcoming World Series on TV, but because the games do not air during the patients' regulation TV time, Nurse Ratched declines the idea. When put to a vote, only McMurphy and Cheswick vote to change their TV time. This leads to another confrontation between McMurphy and the other patients, where he challenges them for their inaction. Goaded on by his bravado and talk of breaking out of the hospital, McMurphy tries to lift a giant control panel in the tub room, cutting his hands on the levers, and eventually giving up after an extreme amount of exertion.

     The following day at group meeting, McMurphy asks for another vote, and while all twenty men who are present and capable of responding vote yes, Nurse Ratched determines he doesn't have a majority vote, as there are forty patients on the ward. McMurphy tries to rouse the unresponsive, Chronic patients to vote, prompting Chief Bromden to raise his hand. Nurse Ratched declares the meeting has already been closed, and does not accept the additional vote.

     At the time when the World Series game is set to begin, McMurphy drags a chair in front of the TV and turns it on. After Nurse Ratched immediately switches it off from her control panel, McMurphy continues to act as if he's watching the baseball game. One by one, the other patients also abandon their duties and sit in front of the blank TV screen, ignoring Nurse Ratched demanding that they get back to work.