The text of The Plague is divided into five parts.
In the town of Oran, thousands of rats, initially unnoticed by the populace, begin to die in the streets. A hysteria develops soon afterward, causing the local newspapers to report the incident. Authorities responding to public pressure order the collection and cremation of the rats, unaware that the collection itself was the catalyst for the spread of the bubonic plague.
The main character, Dr. Bernard Rieux, lives comfortably in an apartment building when strangely the building's concierge, M. Michel, a confidante, dies from a fever. Dr. Rieux consults his colleague, Castel, about the illness until they come to the conclusion that a plague is sweeping the town. They both approach fellow doctors and town authorities about their theory, but are eventually dismissed on the basis of one death. However, as more and more deaths quickly ensue, it becomes apparent that there is an epidemic.
Authorities, including the Prefect, are slow to accept that the situation is serious and quibble over the appropriate action to take. Official notices enacting control measures are posted, but the language used is optimistic and downplays the seriousness of the situation. A "special ward" is opened at the hospital, but its 80 beds are filled within three days. As the death toll begins to rise, more desperate measures are taken. Homes are quarantined; corpses and burials are strictly supervised. A supply of plague serum finally arrives, but there is only enough to treat existing cases and the country's emergency reserves are depleted. When the daily number of deaths jumps to 30, the town is sealed and an outbreak of plague is officially declared.
The town is sealed off. The town gates are shut, rail travel is prohibited, and all mail service is suspended. The use of telephone lines is restricted only to "urgent" calls, leaving short telegrams as the only means of communicating with friends or family outside the town. The separation affects daily activity and depresses the spirit of the townspeople, who begin to feel isolated and introverted, and the plague begins to affect various characters.
One character, Raymond Rambert, devises a plan to escape the city to join his lover in Paris after city officials refused his request to leave. He befriends some underground criminals so that they may smuggle him out of the city. Another character, Father Paneloux, uses the plague as an opportunity to advance his stature in the town by suggesting that the plague was an act of God punishing the citizens' sinful nature. His diatribe falls on the ears of many citizens of the town, who turned to religion in droves but would not have done so under normal circumstances. Cottard, a criminal remorseful enough to attempt suicide yet fearful of being arrested, becomes wealthy as a major smuggler. Meanwhile, Dr. Rieux, a vacationer Jean Tarrou, and a civil servant Joseph Grand exhaustively treat patients in their homes and in the hospital.
Rambert informs Tarrou of his escape plan, but when Tarrou tells him that others in the city, including Dr. Rieux, also have loved ones outside the city whom they are not allowed to see, Rambert becomes sympathetic and changes his mind. He then decides to join Tarrou and Dr. Rieux to help fight the epidemic.
In mid-August, the situation continues to worsen. People try to escape the town, but some are shot by armed sentries. Violence and looting break out on a small scale, and the authorities respond by declaring martial law and imposing a curfew. Funerals are conducted with more and more speed, no ceremony, and little concern for the feelings of the families of the deceased. The inhabitants passively endure their increasing feelings of exile and separation; despondent, they waste away emotionally as well as physically.
In September and October, the town remains at the mercy of the plague. Rieux hears from the sanatorium that his wife's condition is worsening. He also hardens his heart regarding the plague victims so that he can continue to do his work. Cottard, on the other hand, seems to flourish during the plague, because it gives him a sense of being connected to others, since everybody faces the same danger. Cottard and Tarrou attend a performance of Gluck's opera Orpheus and Eurydice, but the actor portraying Orpheus collapses with plague symptoms during the performance.
Rambert finally has a chance to escape, but he decides to stay, saying that he would feel ashamed of himself if he left.
Towards the end of October, Castel's new anti-plague serum is tried for the first time, but it cannot save the life of Othon's young son, who suffers greatly, as Paneloux, Rieux, and Tarrou look on in horror.
Paneloux, who has joined the group of volunteers fighting the plague, gives a second sermon. He addresses the problem of an innocent child's suffering and says it is a test of a Christian's faith, since it requires him either to deny everything or believe everything. He urges the congregation not to give up the struggle but to do everything possible to fight the plague.
A few days after the sermon, Paneloux is taken ill. His symptoms do not conform to those of the plague, but the disease still proves fatal.
Tarrou and Rambert visit one of the isolation camps, where they meet Othon. When Othon's period of quarantine ends, he elects to stay in the camp as a volunteer because this will make him feel less separated from his dead son. Tarrou tells Rieux the story of his life, and the two men go swimming together in the sea. Grand catches the plague and instructs Rieux to burn all his papers. But Grand makes an unexpected recovery, and deaths from the plague start to decline.
By late January, the plague is in full retreat, and the townspeople begin to celebrate the imminent opening of the town gates. Othon, however, does not escape death from the disease. Cottard is distressed by the ending of the epidemic, from which he has profited by shady dealings. Two government employees approach him, and he flees. Despite the epidemic's ending, Tarrou contracts the plague and dies after a heroic struggle. Rieux's wife also dies.
In February, the town gates open and people are reunited with their loved ones from other cities. Rambert is reunited with his wife. Rieux reveals that he is the narrator of the chronicle and that he tried to present an objective view of the events.
Cottard goes mad and shoots at people from his home. He is arrested. Grand begins working on his sentence again. Rieux reflects on the epidemic and reaches the conclusion that there is more to admire than to despise in humans.