1975, in the fictional French town of Ennui-sur-Blasé,[a] Arthur Howitzer Jr., the editor of the magazine The French Dispatch, dies of a heart attack. According to the wishes expressed in his will, publication of the magazine is immediately suspended following one final farewell issue, in which four articles are published, along with an obituary.

The Cycling Reporter Herbsaint Sazerac delivers a cycling tour of Ennui-sur-Blasé, demonstrating several key areas such as the arcade, Le Sans Blague café and a pickpocket's alleyway. He compares the past and the present of each place, demonstrating how much and yet how little has changed in Ennui over time.

The Concrete Masterpiece J.K.L. Berensen delivers a lecture at the art gallery of her former employer, Upshur "Maw" Clampette, in which she details the career of {{user}}. {{user}} , a mentally disturbed artist serving a 50-year sentence in the Ennui prison for double murder, paints an abstract nude portrait of Lea Seydoux, a guard with whom he develops a relationship. Julien Cadazio, an art dealer also serving time for tax evasion, is immediately taken by the painting and buys it despite {{user}} ‘s protests. Upon his release, Cadazio convinces his family of art exhibitors to put it on display, and {{user}} soon becomes a sensation in the art world. Privately, {{user}} struggles with inspiration to the point of near-suicide, and devotes himself to a long-term project at Léa Seydoux‘s challenging.

Three years later, Cadazio, his uncles, Clampette, Berensen, and a mob of artists inspired by {{user}} , all frustrated at the lack of further paintings, bribe their way into the prison to confront him, only to discover that his masterpiece is in fact a series of frescoes in the concrete prison hall. Angered that the paintings are irremovable from the prison, Cadazio gets into a physical altercation with Rosenthaler, but soon comes to appreciate the paintings for what they are, and later arranges for the entire wall to be airlifted out of the prison into a private museum in Kansas, owned by Clampette. For his actions in halting a prison riot that breaks out during the reveal of the paintings, {{user}} is released on probation. Simone also departs after earning a great sum of money for becoming the inspiration and motivation for {{user}} during his incarceration. Léa Seydoux and {{user}} maintain correspondence following his release, but never see each other again.

Revisions to a Manifesto Lucinda Krementz reports on a student protest breaking out in the streets of Ennui that soon boils over into the "Chessboard Revolution", so-called for the students using chess to communicate with the police. While the revolution initially is inspired by petty concerns over access to the girls' dormitory, the traumatic military conscription of one student, Mitch-Mitch, inspires greater uprising.

Despite her insistence on maintaining "journalistic neutrality", Krementz has a brief romance with Zeffirelli, a self-styled leader of the revolt, and secretly helps him write his manifesto and adds an appendix. Juliette, a fellow revolutionary, is unimpressed with his manifesto. After they briefly express their disagreement about its contents, Krementz discovers that Juliette is in fact infatuated with Zeffirelli and is jealous of her closeness with him. She then tells the two to "go make love", which they do.

A few weeks later, Zeffirelli dies attempting repairs on the tower of a revolutionary pirate radio station, and soon a photograph of his likeness becomes symbolic of the movement. Five years later, Krementz translates Mitch-Mitch's theatrical dramatization of his conscription, and Zeffirelli's death, for a National Playhouse production of his play (at the downstairs Knoblock Theatre).

The Private Dining Room of the Police Commissioner During a television interview, Roebuck Wright recounts the story of his attending a private dinner with The Commissaire of the Ennui police force, prepared by legendary police officer/chef Lt. Nescaffier. Nescaffier is a famous specialist in a kind of haute cuisine specifically designed to be eaten by working police officers. The dinner is disrupted when the Commissaire's son Gigi is kidnapped and held for ransom by criminals, led by a failed musician labelled The Chauffeur.

The kidnappers represent the warring criminal syndicates of Ennui-sur-Blasé, and demand the release of an underworld accountant Albert, nicknamed "the Abacus", who possesses their shared financial records. The Abacus is being held in a solitary confinement cell at police headquarters. Wright recollects his own imprisonment in that same cell for his homosexuality, for which he was bailed out by Howitzer and offered a job at the Dispatch.

Following a shoot-out at the kidnapper's hideout, Gigi manages to sneak out a message in Morse code to "send the cook". Lt. Nescaffier is sent into the kidnappers' hideout, ostensibly to provide both them and Gigi with food, but secretly the food is laced with poison. The criminals all succumb to the poison except Gigi and The Chauffeur as neither ate the poisoned radishes, and Nescaffier just barely survives after willingly sampling the food to trick the criminals. The Chauffeur escapes with Gigi, and leads the police on a chase. Gigi manages to escape through the car's sunroof and reunites with his father. During his recovery, Nescaffier saves The Abacus from starving to death by preparing him an omelette, the prisoner having been totally forgotten in the commotion.

Back at the Dispatch office, Howitzer tells Wright to reinsert a deleted segment. In it, a recovering Nescaffier tells Wright that the taste of the poison was unlike anything he had ever eaten before, before they reflect on the state of being foreigners in France, and outsiders to society as a whole. Howitzer and Wright disagree on whether this conversation is the heart of the piece.

Decline and Death In an epilogue, the French Dispatch staff mourn Howitzer's death, but set to work putting together a final issue to honor his memory.

During the closing credits, there is a dedication to the following writers and editors, many of whom were associated with The New Yorker: Harold Ross, William Shawn, Rosamond Bernier, Mavis Gallant, James Baldwin, A. J. Liebling, S. N. Behrman, Lillian Ross, Janet Flanner, Lucy Sante, James Thurber, Joseph Mitchell, Wolcott Gibbs, St. Clair McKelway, Ved Mehta, Brendan Gill, E. B. White, and Katharine White, and additionally to Christophe, writer of the featured song "Aline". Accompanying the credits are covers of the French Dispatch which are reminiscent of The New Yorker covers.