The novel opens in Paris, near the time of World War I, in 1914. Surrounded by the music of a military parade, a young Frenchman, Ferdinand Bardamu, decides, in a moment of heroism, to enlist in the army and join the fight against the Germans. Once at the front, faced with the horrors and absurdity of war, he quickly loses his enthusiasm. Bardamu cannot understand why he is supposed to shoot at the Germans, who have never personally harmed him. Bardamu also realizes he is, in the eyes of his countrymen, something of a coward.

Ferdinand Bardamu is given a reconnaissance mission, during which he meets a fellow soldier named Robinson, who is looking for a way to desert the army. They make plans to escape together, but their efforts fail. Wounded and traumatized by the war, Bardamu returns to Paris for treatment and is given a military medal. This is when he meets Lola, a pretty American nurse who has come to volunteer. Bardamu realizes how much profit stands to be made during wartime by those who are not actually forced to fight in the trenches. When he begins to resist going back to the front, Lola leaves him. Ferdinand's second girlfriend, a violinist named Musyne, who also works entertaining the troops, abandons him during a bombardment of the city.

Once cured of his illness, Ferdinand Bardamu decides to go to Africa, where he is faced with the unbearable heat and boredom of the colonies, as well as the cruel exploitation of the natives. Here, he meets Robinson again and takes over his position as manager of a colonial rubber trading post, a solitary and ramshackle hut in the middle of the African bush. Bardamu falls sick and becomes so delirious with fever that he sets fire to the post and deserts it. Bardamu leaves Africa in a terrible fever, aboard a Spanish ship, which has hired him as an oarsman, should he recover.

The ship docks in New York City, a place Bardamu has always dreamed of visiting. Bardamu manages to stay in the United States, but finds poverty and solitude, instead of the riches and friends of which he had dreamed. After an unfortunate meeting with Lola, he leaves New York for a job in Detroit. Working on the automobile assembly line for Ford, he nearly goes crazy with the mechanical repetitiveness of the work. A generous young prostitute named Molly falls for Bardamu and helps to buy his freedom from the plant. Molly offers to help him settle in the New World with her, but Bardamu's craving for adventure is too strong and he sacrifices his happy life with her in favor of returning to Paris. Bardamu leaves the United States with a heavy heart.

After earning his medical diploma, Bardamu continues to lead an impoverished existence. Bardamu sets up his medical practices in Rancy, a grim, underprivileged suburb. There, he uncovers some of the most desperate and repulsive sides of the human condition. Bardamu becomes involved in a sordid affair with the Henrouilles, a middle-aged couple, seeking to get rid of their elderly, clever mother-in-law. The couple pays Robinson to murder the old woman so that they can rent out her room, but Robinson's clumsiness in setting up the trap for his victim results in an explosion that injures him, leaving him temporarily blinded. Bardamu takes care of Robinson and helps arrange for his exile in Toulouse. Grandmother Henrouille is sent away with him to prevent her from telling the police of the affair.

Bardamu leaves Rancy and gives up practicing medicine for a while. Bardamu visits Robinson in Toulouse, where, surprisingly, his friend is doing well, cooperating with Grandmother Henrouille (his former intended murder victim) in a small business. They work at a small church, showing the mummified corpses in the basement to the tourists. Bardamu meets Robinson's new fiancée, Madelon and, on a whim, has a short affair with her. Despite their romantic betrayals and uncertain loyalties, they all spend a few weeks together on holiday. It ends abruptly when Bardamu hears that Grandmother Henrouille has fallen down the stairs at her job, clearly having been pushed to her death by Robinson, who wanted the business to himself.

Bardamu leaves the unpleasant scene and returns to Paris, where he takes a new job at a psychiatric institute, under the leadership of Dr. Baryton. Unfortunately for Bardamu, Robinson turns up again in a few months and asks to be sheltered at the Institute. Robinson has recovered his sight and left Madelon, who has been pursuing him and threatening to turn him into the police unless he marries her. In an effort to reconcile the three, who have all had quarrels with each other, one of the nurses at the clinic proposes a night at the carnival. Madelon refuses to join in the fun. During the taxi ride home and when Robinson continues to reject her declarations of love as meaningless, she shoots and kills him. After watching his friend die, Bardamu finds himself wondering if Robinson had actually planned for Madelon to shoot him all along. After all, Robinson had sought a way out of the war by surrendering, maybe he was just looking for an easy way out of life, which, thinks Bardamu, in the end is just a carnival full of empty, cheap pleasures meant to distract us from our troubles.