The novel begins with the whining of a mongrel in a Moscow gateway. The dog complains about a dog's life, a well as people's attitude towards homeless animals. The dog also talks at length about a burn wound on his left side made by a cook in the office canteen at the National Economic Council, who spilled some boiling water and scalded him. A poor typist woman, who suffers from bad nutrition and the cold weather, calls the dog Sharik as she passes (literally "small ball"; a common dog's name in Russia). Later, a gentleman shares a piece of a sausage with Sharik, and after such a warmhearted gesture, Sharik agrees to follow the man. The man is revealed to be the important Professor Philip Philippovich Preobrazhensky, and the two arrive at the professor's apartment. At first, the place reminds Sharik of a hospital with its dark corridors and bright lights. Sharik attempts to escape, but he is subdued by the professor and his assistant (later revealed to be Dr. Ivan Arnoldovich Bormenthal), who knock him out and tend to his wounds.
When Sharik comes to, the doctor sees a variety of patients before being visited by the house committee. The house committee, led by a man named Shvonder, tries to shake Profressor Preobrazhensky down and get him to relinquish some of his expansive apartment (in particular, his dining room). In response, Profressor Preobrazhensky calls the chairman of the house committee and demands that Shvonder and company stand down. They leave ashamed, and the whole episode endears Sharik to the professor, who Sharik imagines is a powerful, almost divine authority figure.
Sharik settles into life with Profressor Preobrazhensky, and he is spoiled richly with a wide variety of fine foods. He listens in on Profressor Preobrazhensky as he dines with Dr. Bormenthal and discusses his bourgeois, anti-socialist sympathies. He also becomes acquainted with Zina, the housemaid—who takes him on walks—as well as Darya Petrovna, the house's cook. One Tuesday, however, all of this changes when Dr. Bormenthal calls to say he has acquired goods from someone who recently died. A fuss then ensues in the apartment, with preparations being made for some major event. At the center of it, Sharik soon realizes, is he himself. He is once again knocked out by Dr. Bormenthal and Profressor Preobrazhensky, who then operate on him. Recounted then in grotesque detail is the procedure itself, wherein a pituitary gland and testicles are transplanted from a recently deceased human into Sharik's body. He survives the procedure, but just barely.
In Profressor Preobrazhensky and Dr. Bormenthal's case notes, we are then told of how Sharik not only survived in the wake of the operation (itself meant to test the rejuvenatory potential of transplants), but also how he began to transform entirely into a human being after the procedure. He learned to wear clothing, converse (although crudely), and act like a human in other ways. We are also told of the individual whose organs are now inside Sharik, an indigent Bolshevik criminal named Klim Grigorievich Chugunkin.
Over time, Sharik begins to get on Profressor Preobrazhensky's nerves in a variety of ways. First and foremost, there are his old dog-like habits, which leads him to break Profressor Preobrazhensky's faucet and flood the apartment during the Professor's business hours. Second, there is the fact that Sharikov is ideologically Bolshevik, calling Profressor Preobrazhensky out for his decadence and becoming close with Shvonder of the housing committee. It is Shvonder, for example, who gets Sharik registered officially as someone named Poligraph Poligraphovich Sharikov, supplies him with Bolshevik Engles readings, and gets him work eventually as an animal control officer—albeit one who strangles cats and turns their fur into squirrel coats for the working class. Third, there is Sharik's drunkenness and ill-temper, which leads him to bring strange characters to the Professor's apartment and to even attempt raping Darya and Zina. Finally, the last straw is had when Sharik brings home a frail woman—very heavily implied to be the same typist who passed Sharik in the beginning of the novel—whom he intends to marry and register with. Profressor Preobrazhensky tells this woman the truth and drives her off, which leads Sharik to retaliate by both verbally threatening Profressor Preobrazhensky with a revolver and informing on him to the authorities for his decadent, Menshevik ways.
What Sharik doesn't know, however, is that Profressor Preobrazhensky is friendly with a high officer of the Soviet authorities. This friend of Profressor Preobrazhensky's comes to the apartment and tells the Professor about Sharik's testimony against him, co-signed by Shvonder. Later that day, when Sharik returns from his job, Profressor Preobrazhensky confronts Sharik and tells him to get out of the apartment. This causes Sharik to snap and take out a revolver, threatening the Professor and Dr. Bormenthal. The two spring into action, however, and subdue Sharik in the examination room.
Rumor of this skirmish, seen from the streets and heard from nearby apartments, spreads in following several days. Ten days after the struggle, however, the text's epilogue sees Shvonder appear with some authorities at Profressor Preobrazhensky's apartment. They are looking for Sharik, and suspect that he was murdered by the professor and his staff. Profressor Preobrazhensky disproves their claims, however, by showing them Sharik, now returned to canine form (it is implied that they reversed the initial procedure after their fight). Since there is no disputing that Sharik is, in fact, a dog and not a man—and alive, to boot—no crime can be levied at the profressor. Shvonder and company leave in a frustrated and embarrassed state. The novel then closes with Sharik's narration, returned to its former innocence and canine wonder. He watches Profressor Preobrazhensky tend to some preserved brains in his examination room and thinks of how lucky he is to be set up with such a powerful and successful master.