The play starts in the town square of a small provincial French village. Two friends – the eloquent, intellectual but incredibly prideful Jean, and the simplistic, shy, kind-hearted drunkard Berenger – meet up in a coffee house to talk about an unspecified urgent matter. Instead of talking about what they were supposed to, Jean becomes furious at Berenger's tardiness and drunken state and berates him until a rhinoceros rampages across the square, considerably startling the people there. The people there begin to discuss what has happened when another rhinoceros appears and crushes a woman's cat. This generates incredible outrage and people begin to band together to argue that the presence of these rhinos should not be allowed. The beginning of a mass movement is seen onstage.
Berenger arrives late for work at the local newspaper office, but the newspaper's receptionist Daisy (with whom Berenger is in love), covers for him. At the office, an argument has broken out between the sensitive and logical Dudard and the violent, temperamental Botard; since Botard does not believe a rhinoceros could actually appear in France despite all the claims by eyewitnesses that one did.
Suddenly, Mrs. Bœuf (the wife of a fellow employee) appears to say that her husband has turned into a rhinoceros and that streets are plagued with people who have turned into them. Botard argues against the existence of the so-called "rhinoceritis" movement that Mrs. Bœuf claims is occurring, saying that the local people are too intelligent to be tricked by the empty rhetorics of a mass movement. Despite this, Mr. Bœuf (turned into a rhinoceros) arrives and destroys the staircase that leads out of the office, trapping all the workers and their boss, Mr. Papillion, inside. Mrs. Bœuf joins her husband by jumping down the stairwell while the office-workers escape through a window.
Berenger goes to visit Jean in order to apologize for the previous day's argument they had, but finds him in bed, heavy with a sickness he has never had. The two friends begin to argue again, initially about the possibility of people actually turning into rhinos and then about the morality of the transformations. Jean is initially staunchly against the rhinos, but gradually grows lenient. As the scene progresses, Jean's skin turns greener and greener, the bumps in his head grow into a horn, his voice grows hoarse and he begins to pace around his apartment like a caged beast. Finally, he proclaims that rhinoceros have just as much of a right to life as humans and that "Humanism is dead, those who follow it are just old sentimentalists" before he turns into a rhino himself and chases Berenger out of his apartment.
Everyone in town has succumbed to rhinoceritis save for Berenger, Dudard and Daisy. Berenger is locked up in his apartment, yelling at the rhinos that rush by for having destroyed civilization until Dudard arrives to check on him. Dudard trivializes the transformations by saying that people have the right to choose what they do, even transform; but Berenger insists that the transformations couldn't be voluntary since his friend Jean had initially hated the rhinos and that he was probably brainwashed. Dudard counterargues that people can change their minds and gradually grows more accepting until he concludes that he must "follow [his] peers and [his] leaders" before departing and turning into a rhino.
Just before he departs, Daisy arrives. She and Berenger realize that they are left completely alone – the only humans left in a world of monsters. Berenger professes his love for Daisy and she seems to reciprocate. They attempt, albeit briefly, to have a normal life amongst the rhinoceroses. After Berenger suggests that they attempt to re-populate the human race, Daisy begins to move away from him, suggesting that Berenger doesn't understand love. She comes to believe the rhinoceroses are in the right – they who are truly passionate. Berenger slaps Daisy without thinking, immediately recanting his action. They consider their state with Berenger exclaiming that, "in just a few minutes we have gone through twenty-five years of married life!" They attempt to reconcile, but fail. As Berenger examines himself in a mirror for any evidence of transformation, Daisy quietly leaves to join the rhinoceroses.
Discovering he is completely alone, Berenger laments his behavior with Daisy. In his solitude he begins to doubt his existence – his language, his appearance, and his mind. Alone, he finds himself in the wrong and attempts to change into a rhinoceros. He struggles and fails. He returns to the mirror, face-to-face with his fate and breaks down as he struggles to accept the place he has given himself. Suddenly, he snaps out of it and renews his vow to take on the rhinos. Berenger valiantly shouts "I'm not capitulating!" to the audience before returning to the window to hurl abuse at the passing rhinoceros.