The movie begins in Jerusalem at the Wailing Wall in the 1930s. Famed Belgian detective Hercule Poirot (Kenneth Branagh) attempts to work out who was behind the theft of a religious relic from a room where a priest, a rabbi and an imam were conducting a meeting under the supervision of the Chief of Police. Poirot (who is shown to be fussy, bordering on OCD about everything in his life being balanced, as displayed when he sends back two eggs he'd planned to eat because they were different sizes), works out from a single crack left on the wall that the culprit was actually the Chief of Police (As the religious figures, leading modest lives, had no reason to steal the relic and wore soft shoes unlike the chief) who tries to make a run for it but fails. With the culprit caught and the relic recovered, Poirot looks forward to his upcoming holiday and taking a break from detective work.
Poirot catches a boat from Istanbul, where he makes the acquaintance of a Governess Mary Debenham (Daisy Ridley) while also aboard is a young black doctor named Arbuthnot (Leslie Odom Jr.). When he gets there, he encounters his friend Bouc (Tom Bateman) who is now the director of the famous Orient Express, however, just after the two get reacquainted a telegram arrives for Poirot from London; a case demands his immediate attention. Poirot is unhappy that his long-awaited break is being interrupted, but Bouc offers to take him to France on the Orient Express. The trip will be three days long, and Poirot settles for at least having that long to relax.
Reaching the train, Bouc is surprised to learn that all the compartments have been booked (an uncommon occurrence) however one of the passengers has failed to show on time, so his ticket is forfeit. Also aboard are a myriad of other characters; as well as Debenham and Arbuthnot there is an unpleasant American by the name of Samuel Ratchell (Johnny Depp), his valet Edward Masterman (Derek Jacobi) and secretary Hector MacQueen (Josh Gad), the Austrian Professor Gerhard Hardman (Willem Defoe), American socialite Mrs. Hubbard (Michelle Pfeiffer), Italian car salesman Beniamino Marquez (Manuel Garcia-Rulfo), the elderly Princess Dragomiroff (Judi Dench) and her assistant Hildegarde Schmidt (Olivia Colman), unhappy missionary Pilar Estravados (Penelope Cruz) and finally the Count and Countess Andrenyi (respectively played by Sergei Polunin and Lucy Boynton).
The first night and day pass without incident, although Poirot is put out at having to share his room with MacQueen. The next evening, Ratchett approaches Poirot and requests that he serve as his bodyguard for the duration of the trip as he has been receiving threatening letters and assumes they're from his former clients to whom he sold forged paintings. Poirot, who took an immediate dislike to Ratchett, refuses on the basis he seeks out criminals and won't help them. Ratchett offers increasing amounts of money and even indirectly threatens Poirot with a gun, but Poirot won't be bought or intimidated and leaves in disgust.
That night, Poirot (who now has the room to himself due to MacQueen getting bumped into another) looks forward to a good night's sleep but finds it in short supply; first there is a noise seeming to come from the compartment next to his (Ratchett's), but when the Conductor who goes by the name of Pierre Michel enquires as to it a voice responds that everything is fine. Poirot is also woken up by a bell and a knock, and during the disturbances, he spots a figure in a red kimono running down the hallway. Meanwhile, there is an avalanche which stops the train in its tracks, leaving everyone stranded on the line. Poirot is thrown from his bed, where he spies Marquez picking up spilled photos.
Since the Express was expected to arrive at their next station the following day, everyone will need to wait for a rescue team to be sent. In the morning, Poirot finds out that Ratchett has been murdered in his bed during the night, having been stabbed numerous times in a classic locked-door mystery. Bouc asks Poirot to investigate the case; however, Poirot initially refuses; he was supposed to be on holiday after all. Bouc implores him to look into the murder, as the Yugoslav police will likely look for a scapegoat and may target Marquez or Arbuthnot. Faced with this, an exasperated Poirot agrees. After confirming that no-one left or entered the carriage during the night and that no-one is on the train that shouldn't be, Poirot knows that any of the other passengers or conductor could be the murderer. He takes Bouc as his assistant; as Bouc was sleeping in another carriage, he couldn't be the murderer.
An investigation of the body shows that Ratchett was stabbed twelve times; however the wounds are not consistent... while some are certainly lethal, others are shallow. This implies that the murderer was drunk, but Ratchett was of good physical built, armed and already wary so it's very unlikely he was overpowered. Investigating his room, they find the threatening letters as well as a partially destroyed note connecting Ratchett to the case of Daisy Armstrong. Poirot remembers the case; Daisy Armstrong was a little girl who was kidnapped and then murdered despite the family paying the ransom which caused her mother Sonia (Miranda Raison) to go into premature labor killing both her and her unborn child (with Daisy's father committing suicide soon after). Daisy's murderer was a man called Lanfranco Cassetti who got away with the crime, and Poirot and Bouc soon discover from the evidence that Ratchett was Cassetti and whoever killed him likely had a connection with that case. Some more evidence is found, a blood-stained handkerchief with the initial 'H' and the button from a conductor's uniform is found in Mrs. Hubbard's room (she had previously been claiming someone was in her room). An investigation of Michel's uniform shows all the buttons to be present, so an investigation of everyone's luggage is conducted (except for the Count and Countess as they have diplomatic immunity). The uniform doesn't show up, and Poirot deduces the culprit is trying to outsmart him when the kimono he spotted the previous night is found in his suitcase. Mrs. Hubbard is later stabbed in the back, but the wound is very minor, and she cannot identify who did it. The uniform with the missing button is later found on an overhead rack, leaving that lead at a dead end.
A rescue team arrives and start freeing the Orient Express from the snow. Poirot and Bouc speak to MacQueen and find he had a motive for the murder as he had been skimming money off Cassetti's accounts. They also find a connection to the Daisy Armstrong case; MacQueen's father had attempted to prosecute Armstrong's nursemaid causing her to commit suicide, with his career being destroyed when the truth was known. As his interviews and investigations proceed Poirot finds that many of the passengers had a connection to the Daisy Armstrong; Princess Dragomiroff was Sonia Armstrong's godmother and friend to her mother, Linda Arden, Schmidt was the Armstrong's cook, Arbuthnot was in the Army with Daisy's father, Marquez was the family's chauffer, Pilar was Daisy's nursemaid and had fallen asleep when the girl was abducted, Debenham was Daisy's Governess and Masterman was butler to the Armstrong family. The biggest connection, however, is the Countess Andrenyi... she is Helena Goldenberg, Daisy's aunt. Despite all this, Poirot finds himself unable to narrow down who commited the act.
While questioning Debenham about the murder, he is confronted by Arbuthnot (who is also implied to be Debenham's secret lover) who claims responsibility for the murder. He attempts to shoot Poirot but misses and then flees. Poirot realizes that Arbuthnot never meant to kill him (Arbuthnot was a sharpshooter in the army and would never have missed his shot at such close range) and demands that all the suspects be assembled which they quickly are (in the tunnel, for some reason). Poirot reveals that there are two possible solutions to the murder, and the first is simple yet unlikely... Cassetti was murdered by one of the many enemies he acquired over the years as Ratchett who got aboard the train and then fled after the murder. The second is outlandish but fits the facts better: everyone board was involved in the murder. Poirot has found even more connections to the Daisy Armstrong case; Gerhard Hardman is actually an American detective called Cyrus who was in love with the nurse falsely accused who turns out to have been Michel's sister while Mrs. Hubbard is Linda Arden. He has reasoned that, so that no-one person would have been responsible, all of the suspects entered Cassetti's room and stabbed him in turn as a form of execution, no-one knows exactly who killed him. Arden admits she was responsible for bringing everyone together, determined to make Cassetti pay for what he did to her daughter and granddaughter. Poirot tells Arden that now he is the only person who can expose their plot and challenges someone to shoot him, leaving his gun on the table. Arden picks it up but instead attempts to shoot herself, but the gun isn't loaded as Poirot just wanted to see what she would do. He watches as Arden collapses into tears.
The train is unearthed and continues on its way. Poirot decides that there is no justice to be found in this case; everyone aboard has already suffered greatly from Cassetti's crime, while Cassetti himself was an evil man who had gotten away with murder and deserved what happened to him. He notes that this is one imbalance he will have to live with. When the train reaches the station, Poirot tells the police that his first theory is correct; The murderer was an enemy of Ratchett who has fled. The police believe him, and the passengers continue on their way.
Poirot decides to disembark the train at this point, eager to finally get some rest. Once again, however, his reputation has preceded him, and he is approached by a messenger as he is needed in Egypt due to a death on the Nile. Although tired, Poirot decides to take the case, stopping for a moment to see the Orient Express disappear into the distance.
*CUT TO THE CHASE*
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After much investigating, intrigue and mystery Poirot (Kenneth Branagh) concludes that all twelve of his suspects participated in the murder of Ratchett/Cassetti since they'd all suffered greatly when he murdered Daisy Armstrong years earlier. Deciding they've all suffered enough, and he decides not to reveal this to the police and instead claims Ratchett was killed by someone who fled the train. Poirot's plans for a holiday are curtailed again as he is called to Egypt to investigate a Death on the Nile (get it?).
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