The plot centers around the French Algerian city of Oran as it combats a plague outbreak and is put under a city-wide quarantine.

[1] Camus used as source material the cholera epidemic that killed a large proportion of Oran's population in 1849, but set the novel in the 1940s.

The narrative tone is similar to Kafka's, especially in The Trial, whose individual sentences potentially have multiple meanings; the material often pointedly resonating as stark allegory of phenomenal consciousness and the human condition.

A supply of plague serum finally arrives, but there is only enough to treat existing cases and the country's emergency reserves are depleted.

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.

Meanwhile, Jean Tarrou, a vacationer; Joseph Grand, a civil engineer; and Rieux, exhaustively treat patients in their homes and in the hospital.

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 tend to his bedside in horror.

When Othon's period of quarantine ends, he chooses to stay in the camp as a volunteer because this will make him feel less separated from his dead son.

By late January, the plague is in full retreat and the townspeople begin to celebrate the imminent opening of the town gates.

He reflects on the epidemic and declares he wrote the chronicle "to write simply about what can be learned in the middle of scourges, that there is more to admire in humans than there is to scorn".

[13] Marina Warner notes its larger philosophical themes of "engagement", "paltriness and generosity", "small heroism and large cowardice", and "all kinds of profoundly humanist problems, such as love and goodness, happiness and mutual connection".

[14] Thomas L Hanna and John Loose have separately discussed themes related to Christianity in the novel, with particular respect to Father Paneloux and Dr Rieux.

[21] He has also been an inspiration to the life and career of the French doctor Réjean Thomas, and also to the fictional character of Jeanne Dion, starring in the movie trilogy directed by Bernard Émond (beginning with The Novena).

[24] The novel became a bestseller during the worldwide COVID-19 pandemic of 2020 to the point that its British publisher Penguin Classics reported struggling to keep up with demand.

The prescience of the fictional cordon sanitaire of Oran with real-life COVID-19 lockdowns worldwide brought revived popular attention.

[29] On 13 March 1942, he informed André Malraux that he was writing "a novel on the plague", adding "Said like that it might sound strange, […] but this subject seems so natural to me.