The film integrates various types of artist manifestos from different time periods with contemporary scenarios. Manifestos are depicted by 12 different characters (13 including the prologue voiceover), among them a school teacher, factory worker, choreographer, punk, newsreader, scientist, puppeteer, widow, and homeless man. The film consists of a 4-minute prologue and 12 main segments, each 10:30 minutes long. In each, a character recites parts of manifestos of various political and artistic movements.

The documentary follows the lives of an Inuk, Nanook, and his family as they travel, search for food, and trade in the Ungava Peninsula of northern Quebec, Canada. Nanook, his wife Nyla and their family are introduced as fearless heroes who endure rigors no other race could survive. The audience sees Nanook, often with his family, hunt a walrus, build an igloo, go about his day, and perform other tasks.

The plot involves Gurdjieff and his companions' search for truth in a series of dialogues and vignettes, much as in the book. Unlike the book, these result in a definite climax—Gurdjieff's initiation into the mysterious Sarmoung Brotherhood. The film is noteworthy for making public some glimpses of the Gurdjieff movements.

In 1941, up-and-coming Broadway playwright Barton Fink accepts a contract from Capitol Pictures in Hollywood to write film scripts for a thousand dollars per week. Upon moving to Los Angeles, Fink settles into the cheap Hotel Earle. His room's only decoration is a small painting of a woman on the beach, arm raised to block the sun. Fink is assigned to a wrestling film by his new boss Jack Lipnick, but he finds difficulty in writing for the unfamiliar subject. He is distracted by sounds coming from the room next door, and he phones the front desk to alert them of the disturbing sounds. His neighbor, Charlie Meadows, the source of the noise, visits Fink to apologize. During their conversation, Fink proclaims his affection for "the common man", and Meadows describes his life as an insurance salesman. Still unable to proceed beyond the first lines of his script, Fink consults producer Ben Geisler for advice. Irritated, the frenetic Geisler takes him to lunch and orders him to consult another writer for assistance. Fink meets the novelist W. P. Mayhew by chance in the bathroom. They briefly discuss movie-writing and arrange a second meeting later in the day. Fink later learns from Mayhew's secretary, Audrey Taylor, that Mayhew suffers from alcoholism and that Taylor ghostwrote some of his scripts. With one day left before his meeting with Lipnick to discuss the film, Fink phones Taylor and begs her for assistance. Taylor visits him at the Earle and they have sex. Fink awakens the next morning to find that Taylor has been violently murdered. Horrified, he summons Meadows and asks for help. Meadows is repulsed but disposes of the body and orders Fink to avoid contacting the police. After Fink has a meeting with an unusually supportive Lipnick, Meadows announces to Fink that he is going to New York for several days, and asks him to watch over a package he is leaving behind. Soon afterwards, Fink is visited by two police detectives, who inform him that Meadows's real name is Karl "Madman" Mundt. Mundt is a serial killer whose modus operandi is beheading his victims. Stunned, Fink places the box on his desk without opening it and he begins writing feverishly. Fink produces the entire script in one sitting and he goes out for a night of celebratory dancing, returning to find the detectives in his room, who inform him of Mayhew's murder and accuse Fink of complicity with Mundt. As the hotel is suddenly engulfed in flames, Mundt appears and kills the detectives with a shotgun, after which he mentions that he had paid a visit to Fink's parents and uncle in New York. Fink leaves the still-burning hotel, carrying the box and his script. Shortly thereafter he attempts to telephone his family, but there is no answer. In a final meeting with Lipnick, who has been conscripted by the United States Army Reserve to serve as a colonel in the Second World War, Fink's script (which is suggested to be a nearly word-for-word copy of the Broadway play shown in the opening scene) is lambasted as "a fruity movie about suffering", and he is informed that he is to remain in Los Angeles; although Fink will remain under contract, Capitol Pictures will not produce anything he writes until he "grows up a little". Dazed, Fink wanders onto a beach, still carrying the package. He meets a woman who looks just like the one in the picture on his wall at the Earle, and she asks about the box. He tells her he does not know what it contains nor who owns it. He asks her if she has ever been in pictures, and she says no. She then assumes the pose from the picture on the hotel room wall. In the background, a seagull falls into the water and dies.

Charly Gordon is an intellectually disabled man who lives in Boston. He has a desire to learn and has attended night school for two years, taking a class taught by Alice Kinnian. He learns to read and write, though his spelling and penmanship are poor and he is unable to spell his own name. He works as a janitor at a bakery, where his coworkers amuse themselves by taking advantage of his disability, and he enjoys playing with children at a playground. Alice takes Charly to researchers Dr. Richard Nemur and Dr. Anna Straus, who have been investigating methods for increasing intelligence. Having successfully tested a surgical procedure on a lab mouse named Algernon, they are looking for a human test subject. They put Charly through a battery of aptitude tests and have him try to solve a series of paper mazes while Algernon runs through models of them. Charly consistently loses to Algernon, but is selected for the surgery. After surgery, Charly loses to Algernon again and is frustrated at not immediately becoming smarter. After some time passes, he finally beats Algernon and his intelligence begins to increase. His coworkers tell him to operate a complex machine, hoping that he will break it so they can have the day off, but he successfully operates it. Embarrassed and frightened by his new intelligence, they persuade the bakery owners to fire Charly. Alice continues teaching him, but his intelligence continues to increase and eventually surpasses hers. Lacking emotional maturity, Charly becomes infatuated with Alice and confesses his love for her, but she sharply rejects his advances. He flees in an act of rebellion but eventually returns to Boston, and the two start to consider marriage. Nemur and Straus present their research at a scientific convention. After playing the film of Charly's original aptitude tests, they bring him out for a question-and-answer session. He is now the intellectual equal or superior of everyone in the audience, but he has also developed a cynical view of humanity that the attendees mistake for humor. He reveals that Algernon has lost his enhanced intelligence and died, facts that the research team kept from him, and expects to undergo a similar decline. Fleeing the convention and seeing hallucinations of his previous self everywhere, Charly stops to help a busboy pick up a tray of dropped glasses after observing that he is intellectually disabled. Charly overhears Alice, Nemur, and Straus discussing his situation and offers to assist in finding a way to preserve his intelligence, but their combined efforts prove fruitless. He falls into a depression and asks Alice never to visit him again. Some time later, Alice sees Charly playing with children on the playground, having fully regressed to his original level of disability.