The novel follows the eponymous murders and their investigation as seen by Arthur Hastings, Poirot's old friend. Poirot receives typed letters signed by A.B.C.. In each is given the date and location of the next murder. A.B.C. moves alphabetically: Alice Ascher is a tobacco shop owner killed in her shop in Andover, Betty Barnard is a flirty waitress killed in Bexhill, and Sir Carmichael Clarke is a wealthy man killed at his home in Churston. A.B.C. leaves an ABC railway guide with each victim. Poirot has two doubts in his mind: a) Why would A.B.C. write to him instead of the Scotland Yard or any reputed newspaper?, and b) Why did a meticulous man like A.B.C. misspell Poirot's address on the Churston letter?
Each chapter narrated by Hastings is followed by a description of events in the life of Alexander Bonaparte Cust, a travelling salesman. Cust, an epileptic who had served in the war, was rendered incapable of doing many kinds of work due to a head injury which made him prone to memory blackouts and constant headaches. Meanwhile, Poirot forms a "Legion" of relatives of the deceased in hopes of uncovering new information. Inspector Crome, who doubts Poirot's detective abilities and Dr Thomson, who tries to profile this serial killer, are part of the police team.