Eight strangers are invited by a mysterious person named U. N. Owen to a luxurious mansion on an island off the coast of Devon. Waiting for them on the island are the housekeeping couple, Mr. and Mrs. Rogers. After dinner, the group hears a recording in which a disembodied voice exposes each of them as a murderer whose crime has has gone undetected and unpunished. Playboy Tony Marston is accused of driving recklessly and causing the deaths of two young people; Mr. and Mrs. Rogers are accused of murdering their aged employer by withholding medication from her; General Macarthur is accused of arranging for the death of a fellow officer; Emily Brent is blamed for the death of her maidservant; Justice Wargrave is blamed for sentencing a possibly innocent man to death; Dr. Armstrong is accused of killing a patient; former policeman William Blore is accused of knowingly sending an innocent man to prison, where he died; soldier of fortune Philip Lombard is accused of allowing native Africans to die of starvation; and former governess Vera Claythorne is blamed for the drowning death of a boy in her care.

The guests defend themselves, determined to preserve their status as acceptable members of English society. Lombard justifies the deaths of the natives in modern, social Darwinist terms, citing the law of self-preservation and the superiority of the Anglo-Saxon race, while Blore asserts that he was simply doing his job. Armstrong admits his guilt, but uses his inebriated condition as an excuse. Marston insisted the deaths of the two young people were accidental.

Marston soon dies from drinking cyanide-laced whiskey. Justice Wargrave immediately takes command, suggesting one of the group is in fact “Mr. Owen,” who is toying with them sadistically. Comparing notes, they realize that none of them knows their host and that his name, U. N. Owen, translates into “unknown.” Shaken, the guests further reflect on the accusations against them. Rogers admits that he and his wife inherited money from the woman from whom they withheld medicine; his wife’s nervous demeanor further confirms their guilt. General Macarthur breaks down, admitting that the young man he sent to his certain death was his wife’s lover.

Ten figurines are arranged on the mansion’s dining room table, representations of the characters in a nursery rhyme that is also framed and hung in each guest’s bedroom. This nursery rhyme, originally “Ten Little Niggers,” was changed to “Ten Little Indians” in the American edition of the novel. In the twenty-first century, some editions changed the rhyme once more to “Ten Little Soldiers.” In each case, the rhyme features the deaths of ten little boys, counting the number of boys who remain alive at the end of each verse. The rhyme ends when all ten are dead, “and then there were none.”

Vera Claythorne notes the similarity between Marston’s poisoning and the death of the first boy in the rhyme, who chokes to death. The next day, the group discovers that Ethel Rogers has died from an overdose of sleeping pills, matching the second little boy’s death by “oversleeping.” The survivors also find that only eight china figurines are left on the table; they begin to fear that there will be successive murders, each one matching the next verse in the rhyme.

A violent storm prevents anyone from coming to or leaving the island. As the pressure builds, Emily admits that a maidservant she had dismissed because she was pregnant and unmarried had subsequently committed suicide. A mood of fear and suspicion intensifies. General Macarthur, increasingly passive and penitential, is found dead; the next day, Rogers is also found dead. Each death conforms to the manner of death of the next little boy in the nursery rhyme. Each time, a figurine disappears.

Confessions and deaths continue to accumulate. Blore admits to Lombard that he had indeed caused an innocent man to be sent to jail. Emily Brent is found dead from an injection of poison that conforms to the “bee sting” death of the fifth little boy in the rhyme. That evening, the judge is discovered dead of a gunshot to the head, corresponding to the sixth little boy in the rhyme. Soon after, Armstrong disappears. The next day, Vera confesses that she deliberately let the boy she was looking after swim out too far and drown so that her lover could inherit the boy’s money.

Vera and Lombard find Blore felled by a bear-shaped clock thrown from a window, a death that conforms to the “bear hug” from which the eighth little boy dies. Neither of them was in a position to commit this crime. When the missing Dr. Armstrong’s body washes up on the shore, however, Vera and Lombard are each irrationally convinced that the other is the murderer. The quick-witted Vera seizes Lombard’s gun and shoots him. She returns to the house, finds a noose waiting for her, and understands that she is meant to die as the tenth boy did in the nursery rhyme. Emotionally exhausted and pushed to the brink of madness, Vera hangs herself.

The discovery of the bodies on the island baffles the police until a letter in a bottle is found by a fishing trawler and sent to Scotland Yard. It is a manuscript by Justice Wargrave, who confesses that he lured his victims to the island to punish them in a way that the law could not. He convinced the gullible Dr. Armstrong to help him fake his death, later murdering him by throwing him off a cliff into the sea. After making sure Vera would commit suicide, the terminally ill Wargrave hastened his death by shooting himself in the head in exactly the same manner in which he appeared to have been shot earlier. His gloating confession reveals a sociopathic temperament hiding behind his cloak of judicial respectability.