The novel opens by introducing the reader to an alcoholic vagrant, resting in an abandoned and forgotten lock-keeper's house by a canal. As he is ruminating over the injustices inflicted upon him in his life, he is suddenly set upon by a pack of black rats the size of small dogs, and is devoured alive.
Harris, a young East London art teacher, notices that one of his students has a bloodied bandage around his hand. When he enquires as to what caused the damage, the student answers that he was attacked by a rat. Meanwhile, a baby girl and her dog are killed by the giant rats, now aided by packs of smaller black rats. The girl's mother rescues her daughter's mutilated body, but not before sustaining bites as well. Harris takes the student to the hospital and sees the grieving mother with her dead child. According to the doctor, the number of seemingly unprovoked rat attacks has strangely increased.
The next rat attack occurs at the remains of a bombsite, where a group of squabbling vagrants are slaughtered. Harris is visited at work by the Minister of Health, Mr. Foskins, who reveals that the bitten student, and all the other surviving victims of rat attacks, died of a mysterious disease 24 hours after being bitten. Foskins asks Harris to keep the existence of the disease a secret and lead an exterminator named Ferris to the area where the student had been bitten. Accompanied by Ferris, Harris goes to the canal described by the student and sights a group of giant rats. Harris attempts to contact the police, while Ferris follows the rats, who then attack and kill him.
The rat attacks become increasingly more daring, as more and more public places are attacked. A tube station is assaulted, leaving few survivors. Next, Harris' own school is attacked, resulting in the death of the headmaster. With the existence of the rats' disease now becoming public knowledge, a meeting is held, in which a young researcher by the name of Stephen Howard comes up with the idea of using a virus to infect the rats. The virus is injected into several puppies, which are left in areas of the attacks. This results in the deaths of thousands of rats, which crawl to the surface to die. A few weeks later however, the rats adapt to the virus, at the same time losing the toxicity of their bites. The rats brutally attack a cinema and overrun the London Zoo. Based on the fact that rats communicate with each other using ultrasound, a plan is formulated to use ultrasonic machines to lure the rats into poison gas chambers.
Foskins is dismissed as Health Minister and reveals to Harris that he has been investigating possible clues as to the rats' origins and comes to the conclusion that they were illegally smuggled into the country by a zoologist named William Bartlett Schiller from an island near New Guinea which had been near some nuclear tests. At his home by an East London canal, Schiller had bred these mutant rats with common black rats, producing a new and deadly strain. They later killed him and escaped.
Pursuing the disgraced health minister past waves of entranced rats, Harris finds the abandoned house and enters it. He goes into the cellar and finds Foskins' corpse being devoured by rats of unusually great size. He kills them after a bloody battle and discovers the rats' alpha hidden in the shadows; a white, hairless and obese rat with two heads. Harris kills the creature with an axe in a fit of rage and leaves.
The epilogue indicates that one female rat survived the purge by being trapped in the basement of a grocery shop. There, it gives birth to a new litter, including a new white two-headed rat.
