In the winter of 1934, Hercule Poirot (Kenneth Branagh), a famous Belgian detective, plans to take a vacation after solving an important case at Jerusalem. Going to Istanbul, Poirot meets with his friend, Bouc (Tom Bateman), director of Orient Express. Receiving a telegram from London on a very important case, Poirot has to return home and Bouc offers him a ticket in the unusual Express. Poirot is approached by Samuel Ratchett (Johnny Depp), an unpleasant American businessman who asks him to be a bodyguard for three days as long as the trip lasts.
He would have received some letters of threat and wants Poirot to protect him during the journey, but he refuses the proposal. In that one, Poirot hears some strange noises coming from Ratchett’s compartment and sees a woman in red kimono running through the hallway. It does not take long until an avalanche is created that causes the train to derail and leaves the passengers isolated in the wilderness.
The next morning, Poirot finds out that Ratchett was killed during the night, being stabbed several times. Poirot and Bouc investigate the murder, the latter not being in the suspects circle because he slept in another wagon. The evidence on the spot indicates that Ratchett was killed by a single individual, and one of the passers-by, Ms. Hubbard (Michelle Pfeiffer), claiming that the man was also in her room during the night. Poirot discovers a partially destroyed note that connects Ratchett with the case of Daisy Armstrong, a kid kidnapped and in return for a reward.