Hercule Poirot, private detective and retired Belgian police officer, boards the Taurus Express train to Stamboul (Istanbul). On the train there are two other passengers, Mary Debenham and Colonel Arbuthnot. The two act as if they are strangers, but Poirot observes behavior that suggests that they are not. Poirot is suspicious of the couple. The train arrives in Stamboul and Poirot checks in at the Tokatlian Hotel. As soon as Poirot arrives he receives a telegram summoning him back to London. While waiting at the hotel for the next train, Poirot bumps into an old friend, M. Bouc, head of the Wagon Lit. M. Bouc arranges a space for Poirot on the Orient Express. In the dining room of the Tokatlian Hotel, Poirot first spots Ratchett and Hector McQueen eating dinner. Poirot know that Ratchett is an evil man and he describes him to M. Bouc as an animal.

Poirot board the Orient Express. He is forced to ride in a second-class cabin because the train is unusually full. Ratchett and Hector McQueen are also aboard the train. Ratchett approaches Poirot and asks if he will work for him, Ratchett tells Poirot he has been receiving threatening letters and that someone is trying to kill him. Poirot refuses the case. M. Bouc has taken the last first class cabin, but arranges to be moved to a separate coach and gives Poirot his space in first class. The first night Poirot sleeps in first class, he observes some strange occurrences. Early in the morning, Poirot is wakened by a cry from Ratchett's compartment next to him. The wagon lit conductor responds knocks on Ratchett's door and a voice from inside responds, "Ce n'est rien. Je me suis trompe" (It is nothing. I am mistaken). Poirot has difficulty sleeping because there is a peculiar silence on the train. Mrs. Hubbard rings her bell and tells the conductor a man is in her room. Poirot rings his bell for water and is informed by the conductor that the train is stuck in a snow bank. Poirot hears a loud thump next door.

The next morning, the train still stopped, M. Bouc informs Poirot that Ratchett has been murdered and the murderer is still aboard the train. Poirot tells M. Bouc he will investigate the case. Poirot first examines Ratchett's body and compartment. Ratchett has twelve stab wounds. The window is left open in Ratchett's compartment, presumably to make the investigators think the murderer escaped out the window, but there are no footprints outside the window in the snow. A handkerchief with the initial "H" is found in the compartment, a pipe cleaner, a round match different from the matches Ratchett used and a charred piece of paper with the name "Armstrong" on it.

The piece of paper with the word Armstrong on it helps Poirot figure out who Ratchett really is and why someone would want to murder him. A few years back, a man named Cassetti kidnapped a three-year old girl, Daisy Armstrong. Cassetti collected a ransom from the wealthy Armstrong family, but killed the child anyways. Poirot concludes that Ratchett is Cassetti.

The interviews start with the Wagon Lit conductor, then Hector McQueen. Poirot knows that McQueen is involved with the case because he knows about the Armstrong note found in Ratchett's compartment, Hector is surprised that Poirot found the note because he thought it had been completely destroyed. He interviews Masterman and then Mrs. Hubbard. Mrs. Hubbard claims that the murderer was in her cabin. All of the passengers give Poirot suitable alibis during their interviews, although a few suspicious elements are brought to light: many passengers observed a woman in a red kimono walking down the hallway the night of the murder, but no one admits they have a red kimono. Mrs. Hubbard tells Poirot she had Greta Ohlsson lock the communicating door between she and Ratchett. Hildegarde Schmidt bumped into a stranger wearing a Wagon Lit jacket.

Poirot checks every passenger's luggage. During the check he notices a few interesting things: the label on Countess Andrenyi's luggage is wet, a Wagon Lit uniform is found in Hildegarde Schmidt's bag and, lastly, the red kimono is found in Poirot's own luggage.

After the luggage check, Poirot, Dr. Constantine and M. Bouc review the facts of the case and develop a list of questions. With the evidence and questions in mind, Poirot sits and thinks about the case. When he surfaces from a somewhat trance-like state, Poirot has discovered the solution to the case. Before he reveals this solution in full, he calls in several people and reveals their true identities. Poirot discovers Countess Andrenyi is Helena Goldenberg, aunt of Daisy Armstrong. She wet her luggage label and obscured her name, in an effort to conceal her identity. Also, Mary Debenham was Daisy's governess, Antonio Foscanelli was the Armstrong's chaffer, Masterman the valet, and Greta Ohlsson was Daisy Armstrong's nurse. Princess Dragomiroff claims her handkerchief from Poirot, the same found in Ratchett's compartment.

Poirot gathers all of the passengers into the dining car and propounds two possible solutions. The fist solution is that a stranger entered the train at Vincovci and killed Ratchett. The second solution is that all of the passengers aboard the Orient Express were involved with the murder. He argues that twelve of the thirteen passengers, all close to the Armstrong case, killed Ratchett to avenge the murder of Daisy Armstrong. Mrs. Hubbard, revealed as Linda Arden, admits that the second solution is correct. Poirot suggests that M. Bouc and Dr. Constantine tell the police that the first solution is correct to protect the family. M. Bouc and Dr. Constantine accept Poirot's suggestion.