1930. A baby, Daisy Armstrong, is kidnapped from her home in Long Island, New York. Newspapers report that despite a ransom being paid, Daisy is slain.

5 years later, Istanbul. Detective Hercule Poirot meets his friend Bianchi, a railway director. Bianchi secures a place for Poirot on the Orient Express. Passengers board the train, including Ratchett, a wealthy American, his secretary, Hector McQueen, and manservant, Beddoes; Mrs Hubbard, an American lady; Greta Ohlsson, a Swedish missionary; Princess Dragomiroff and her maid, Hildegarde Schmidt; the Hungarian Count Andrenyi and his wife; Colonel Arbuthnott of the British army; and Miss Debenham, an English teacher. French conductor Pierre greets them.

In the dining car, Ratchett introduces himself to Poirot, explaining that his life has been anonymously threatened. Poirot is offered $15,000 to be Ratchett's bodyguard, but declines.

That night, Poirot, whose compartment neighbours Ratchett's, is woken by a noise. He sees Pierre talking to Ratchett through a closed compartment door. Later, Mrs Hubbard complains that she saw a man in her compartment. The following morning, Beddoes and Pierre discover Ratchett murdered. Passengers are told that the train is snowbound in Yugoslavia.

Doctor Constantine and Bianchi, staying in a separate car, join Poirot in Ratchett's compartment. Ratchett has been poisoned, then stabbed 12 times. Time of death is estimated between midnight and 2am. Poirot remembers Ratchett cried out around 12:40am, apparently after a nightmare. Bianchi asks Poirot to solve the murder. Poirot agrees, asking for the passengers' passports.

Mrs Hubbard suggests that a man gained access to Ratchett's compartment through her room. The doctor explains the stab wounds differ in strength, possibly suggesting more than one murderer. Poirot deciphers a burnt note, revealing the letters "AISY ARMS."

The note, Poirot deduces, refers to Daisy Armstrong. Poirot recounts the story of her kidnapping to Bianchi, adding that before Daisy's murderer was executed, he disclosed the name of the gangster behind the crime, Cassetti - Ratchett's real identity. Due to the shock of Daisy's murder, Mrs Sonia Armstrong died, prematurely giving birth to a stillborn child. Her husband, Colonel Hamish Armstrong, shot himself, and their French maid, under suspicion, committed suicide. Ratchett was therefore responsible for five deaths.

Poirot interviews the passengers, uncovering clues. Pierre's wife died of grief after their daughter's death. McQueen knew Mrs Armstrong, whom he regarded as a mother. Mrs Hubbard shows Poirot a tunic button from a train attendant's uniform, found in her room. Princess Dragomiroff reveals that she was the godmother of Mrs Armstrong, and is a friend of her mother, the actress, Linda Arden. She also reveals that Mrs Armstrong had a younger sister. The Princess's maid, Hildegarde, knew the Armstrongs' maid, Paulette. In Hildegarde's room, the uniform with a missing button is found, complete with passkey.

Colonel Arbuthnott and Miss Debenham admit to being lovers. Signor Foscarelli, an Italian passenger, suggests that Cassetti was mafia. Mrs Hubbard discovers a blood-stained dagger in her make-up bag. Poirot interviews the last passenger, Cyrus Hardman, who claims he was Ratchett's bodyguard. Poirot shows him a picture of French maid Paulette, which upsets him.

After the passengers are gathered in the dining car, Poirot suggests the most obvious solution, that the murderer was a rival Mafioso, who killed Ratchett before leaving the train. There is also a more complex answer. All the passengers in Ratchett's car were associated with the Armstrong family, including Beddoes, who was Colonel Armstrong's manservant in the army; Miss Debenham, the Armstrongs' secretary; Countess Andrenyi, the surviving sister of Mrs Armstrong; and Hildegarde, the Armstrong's cook. Colonel Arbuthnott knew Colonel Armstrong from the army, Hardman was Paulette's lover, Paulette was Pierre's daughter, Greta had nursed Daisy, Foscarelli was the family chauffeur, and Mrs Hubbard is Linda Arden, Mrs Armstrong's mother. They killed Cassetti for revenge.

It was McQueen who poisoned Ratchett, after which each of the car's passengers in turn, as well as Pierre, stabbed him. Evidence was faked to make Poirot believe the murder was committed before 1.15am, a period for which all had alibis.

Poirot asks Bianchi to choose a solution for the police, but suggests using the first explanation. Bianchi agrees, and the passengers celebrate. The snow is cleared and the train sets off.