The novel is set in England in 1916 at Styles Court, an Essex country manor (also the setting of Curtain, Poirot's last case).
Upon her husband's death, the wealthy widow, Emily Agnes Cavendish, inherited a life estate in Styles as well as the outright inheritance of the larger part of the late Mr. Cavendish's income. Mrs. Cavendish became Mrs. Inglethorp upon her recent remarriage to a much younger man, Alfred Inglethorp. Emily's two stepsons, John Cavendish and Lawrence Cavendish, as well as John's wife Mary Cavendish and several other people, also live at Styles. John Cavendish is the vested remainderman of Styles; that is, the property will pass to him automatically upon his stepmother's decease, as per his late father's will. The income left to Mrs Inglethorp by her late husband would be distributed as per Mrs. Inglethorp's own will.
Late one night, the residents of Styles wake to find Emily Inglethorp dying of what proves to be strychnine poisoning. Lieutenant Hastings, a house guest, enlists the help of his friend Hercule Poirot, who is staying in the nearby village, Styles St. Mary. Poirot pieces together events surrounding the murder. On the day she was killed, Emily Agnes Inglethorp was overheard arguing with someone, most likely her husband, Alfred Inglethorp, or her stepson, John. Afterwards, she seemed quite distressed and, apparently, made a new will — which no one can find. She ate little at dinner and retired early to her room with her document case. The case was later forced open by someone and a document removed. Alfred Inglethorp left Styles earlier in the evening and stayed overnight in the nearby village, so was not present when the poisoning occurred. Nobody can explain how or when the strychnine was administered to Mrs. Inglethorp.
At first, Alfred is the prime suspect. He has the most to gain financially from his wife's death, and, since he is so much younger than Emily was, the Cavendishes already suspect him as a fortune hunter. Evelyn Howard, Emily's companion, seems to hate him most of all. His behaviour, too, is suspicious; he openly purchased strychnine in the village before Emily was poisoned, and although he denies it, he refuses to provide an alibi. The police are keen to arrest him, but Poirot intervenes by proving he could not have purchased the poison. Scotland Yard police later arrest Emily Inglethorp’s oldest stepson, John Cavendish. He inherits under the terms of her will, and there is evidence to suggest he also had obtained poison.
Poirot clears Cavendish by proving it was, after all, Alfred Inglethorp who committed the crime, assisted by Evelyn Howard, who turns out to be his kissing cousin not his enemy. The guilty pair poisoned Emily by adding a precipitating agent, bromide (obtained from Mrs Inglethorp's sleeping powder), to her regular evening medicine, causing its normally innocuous strychnine constituents to sink to the bottom of the bottle where they were finally consumed in a single, lethal dose. Their plan had been for Alfred Inglethorp to incriminate himself with false evidence, which could then be refuted at his trial. Once acquitted, due to double jeopardy, he could not be tried for the crime a second time should any genuine evidence against him be subsequently discovered, hence prompting Poirot to keep him out of prison when he realised that Alfred wanted to be arrested.
Inspector Japp is the Scotland Yard man on the scene, beginning his long association with Hercule Poirot.