Set in 1941, Barton Fink is Jewish playwright from New York whose most recent work, Bare Ruined Choirs, has been ruled a success by critics and audiences alike. He, however, feels the play is “merely adequate” and dreams of creating a work that truly captures something real about the experience of the “common man.” His agent, Garland Stanford, alerts him to a job offer in Hollywood as a screenwriter for Capitol Pictures. Though initially insulted by the notion of working in Hollywood, Barton accepts in hopes of making a difference with a much larger audience.

To live modestly in Los Angeles, or at least to avoid what he perceives as the distasteful Hollywoodesque characteristics of southern California, Barton takes up indefinite residence at the Earle, a rundown hotel suspiciously absent of guests other than Barton and his next-door neighbor Charlie Meadows. Though inexperienced with film and screenwriting, his new boss, Jack Lipnick, believes Barton will easily make the transition and assigns him a script for a wrestling picture starring well-known actor Wallace Beery.

Barton’s progress with the script is obstructed by an unshakeable case of writer’s block. His writing attempts are thwarted by unexpected interruptions mostly from Charlie and his other, off-screen neighbors. Barton and Charlie’s initial introduction is a confrontational affair because they only meet after Barton calls the front desk to complain about the noise Charlie is making next door (laughing and possibly crying). This is Barton’s failed attempt at silencing Charlie without having to personally confront him. After being hushed by hotel staff, Charlie confronts Barton about the complaint. He appears to forgive Barton and afterwards they develop what, at first, seems to be a healthy and mutually beneficial friendship. However, Charlie’s constant interruptions thwart Barton’s attempts at writing. This causes Barton’s stress level to rise as he becomes increasingly overwhelmed by his inability to produce.

Barton eventually approaches well-known novelist W. P. Mayhew for assistance but Mayhew’s apathy for Hollywood and rampant alcoholism renders him a useless resource. Facing the impending deadline of meeting with Lipnick, Barton, instead, turns to Mayhew’s assistant and lover, Audrey Taylor, and calls upon her in a moment of panic for help. She visits his room and confesses she authored Mayhew’s recent works and the two engage in sex instead of writing. Barton awakens and is shocked to find that Audrey has been murdered in his bed while he slept. After a brief emotional breakdown, Charlie offers to help and “takes care of” Audrey’s bloody corpse.

Completely shaken by Audrey’s puzzling murder and his complete lack of writing progress, Barton buys time by convincing Lipnick that sharing his current progress could destroy his conception of the work before having time to perfectly articulate it. Meanwhile, Charlie travels to New York for vague reasons relating to his insurance job, further saddening Barton who will now be without his only friend. Notably, Charlie leaves Barton with a box supposedly containing “everything that’s important to a guy.” Bad news continues when two detectives reveal “Charlie” is actually a wanted murderer by the name of Karl “Madman” Mundt. The detectives suspect Charlie murdered and decapitated Audrey. After Barton learns of Charlie’s lies, he inspects and shakes Charlie’s box which sounds like it only contains one large object (possibly Audrey’s head). At the height of Barton’s mounting pressure, he finally summons the creative energy required to write and finish his script in a single, passionate effort. Barton celebrates his victory as a writer by attending a USO dance where he somehow initiates a fistfight between the army and navy. He returns home to find the detectives have broken into his room, seen his blood-stained mattress, and read his recently completed script. They accuse him of being Charlie’s accomplice, handcuff him to his bed, and confront Charlie who has returned and now stands in the hallway. Charlie’s return is accompanied by a heat increase at the hotel that eventually sets the walls of the hallway ablaze as he runs down its length to shoot the detectives. Charlie then finally confronts Barton about never listening to him and admonishes him for coming into his home (the Earle) and complaining about noise. Charlie, once again, forgives him easily and frees him from the handcuffs. Before returning to his own room, Charlie implies he may have killed Barton’s family while on his business trip. Dismayed and defeated, Barton slowly exits the flame-ridden hallway of the hotel carrying his completed manuscript and Charlie’s box. In the penultimate scene, Barton’s script is rejected by Lipnick who tells him his work will never be published nor will he be released from his contract until he starts writing works that appeal to Capitol Pictures’ target audience. The final scene involves Barton walking along a sunny beach, in his brown suit, with only Charlie’s box in hand. A woman, resembling the woman in an image that hung above his desk, interacts with him briefly. Barton expresses his ignorance of both the box’s contents and owner and the film ends with her turning to face the beach while striking the same pose as the woman in the image above Barton’s desk.