Publisher George Caldwell boards the Silver Streak, a train traveling from Los Angeles, California, to Chicago, Illinois, and looks forward to a restful journey. When Ralston, a porter, shows George to his compartment, the door to the adjoining room opens accidentally, revealing fellow passenger Hilly Burns in her underwear. As Ralston leaves, he tells George not to expect any excitement for the next two days. George visits the club car, where he meets vitamin salesman Bob Sweet, who describes the train as “a cathouse on wheels,” full of eager women looking for companionship. When Sweet attempts to demonstrate his point with Hilly, she pours a drink down his pants. Later, in the dining car, Hilly asks to join George at his table, where they discuss the purposes for their trip: George, a publisher of instructional books, is going to his sister’s wedding, and Hilly is the personal secretary to Prof. Arthur Schreiner, who is to introduce his definitive tome on Rembrandt at the Art Institute of Chicago. Hilly’s attraction to George is immediate, and after sharing a bottle of champagne and ordering two more, they retire to their adjoining compartments, which become one large room with the removal of a partition. Their lovemaking is interrupted when George sees a dead man dangling upside down outside the window, though Hilly believes George is hallucinating from too much champagne. George awakens early the next morning and peruses a copy of Schreiner’s book, given to Hilly for safekeeping. A manila envelope falls from it, which George replaces before noticing that the author’s photograph on the book jacket and the dead man are identical. George wakes Hilly with his revelation, but she sleepily insists that he imagined the corpse, and suggests that he visit the professor’s compartment as proof. When George reaches the compartment, it is being ransacked by an ill-tempered man named Mr. Whiney and a metal-toothed giant named Reace; Schreiner is nowhere in sight. After Whiney and George exchange threats, Reace throws George from the train. George comes upon a small farm run by Rita Babtree, who listens to his story and offers to take him into the nearby town of Staveley, New Mexico, if he milks her cow. Rita flies George to Staveley in her biplane and he secretly boards the train when it passes through town. George enters the dining car and is devastated at the sight of Hilly with another man. As George turns to leave, Bob Sweet invites him to lunch, and identifies Hilly’s companion as Roger Devereau, a renowned expert in fine art. When Devereau and Hilly leave the car, George follows her into her compartment. Hilly is happy to see him, expressing her concern over his disappearance. As George warns Hilly of the danger she could be facing, Devereaux enters and apologizes on behalf of Reace. Devereaux explains that Reace and Whiney are in his employ and were simply looking for some papers that Schreiner had misplaced when George walked in on them. When George asserts that he saw Schreiner’s body the previous night, the professor appears. George is embarrassed and apologizes for meddling, promising Devereaux that he will mind his own business for the remainder of the trip. Hilly asks George to join them for dinner, but George declines and heads to the club car. In George’s absence, Devereaux slaps Hilly across the face, eliciting a chuckle from Whiney. Later, Sweet finds George in the club car drinking heavily, and questions George on his disappearance. Sweet reveals himself to be a federal agent named Bob Stevens, who has been trailing Devereau for more than two years. According to Sweet, Schreiner was murdered because his Rembrandt biography contains information that would ruin Devereau. Also, Whiney and Reace were searching the professor’s compartment for several letters, written by Rembrandt, proving that two paintings authenticated by Devereau were forgeries. Remembering the manila envelope, George takes Sweet to Hilly’s compartment, where they find the Rembrandt papers inside Schreiner’s book. Sweet believes that Hilly will be killed when they reach Chicago, so he instructs George to take her off the train at the next station. As the train passes through a tunnel, a shot is heard in the dark, leaving Sweet on the floor, dying. He gives his gun to George, whom he suspects was the intended target. Ralston enters to see George holding a gun over Sweet's body and runs into the corridor proclaiming that a killer is on board. George runs after Ralston protesting his innocence, and is seen by Reace, who chases him into the baggage car and onto the roof. Along the way, George loses his gun but finds a spear gun, which he uses to kill Reace before falling from the train. In the next town, Sheriff Oliver Chauncey attempts to arrest George, who in turn steals Chauncey’s gun and police car. George is aided in his escape by Grover Muldoon, an African American thief hiding in the back seat. They elude the police and cross the state line. George and Grover arrive at a Kansas City, Missouri, train station to find police stationed throughout and newspaper headlines accusing George of Sweet’s murder. Grover uses shoe polish to disguise George as an African American, and they board the Silver Streak without interference. While Grover searches for a porter’s uniform, George removes his disguise and enters Hilly’s compartment, where he is clubbed from behind. George awakens in a dining car with Devereau and Hilly. Devereau now has the Rembrandt letters, and he plans to kill George and Hilly in a staged murder-suicide, leaving evidence that they killed Schreiner. Grover enters dressed as a waiter and holds Devereau at gunpoint. The group goes to the baggage car to retrieve the letters from Devereau’s safe, but Johnson, Schreiner’s double, comes to his employer’s defense, forcing George and Grover to jump off the train. Hilly is held prisoner while Whiney and Johnson disconnect all of the emergency brakes on the train, ensuring that Devereau reaches his rendezvous with a helicopter in Rockdale, Illinois, on time. Meanwhile, George and Grover are arrested by a police officer, who takes them to the makeshift headquarters of federal agents on the Devereau case. After George informs the agents of Devereau’s plans, the chief arranges to stop the train at Harris Mill Junction, Illinois, evacuate the passengers and crew, and arrest Devereau. George leaves with the agents, while Grover returns to Kansas City. When the train stops, Devereau and his men plot to commandeer the engine, but are interrupted by Ralston, whom they pistol-whip. As the train empties, the agents fire on the criminals, and Whiney is shot. Grover reappears, and he and George board the train to rescue Hilly. After Devereau orders the engineer to start the train, the gunfight continues as agents in helicopters give chase. On board, George kills Johnson; Devereau kills the engineer for trying to escape, and weights the throttle with a toolbox. A bullet wound from the chief disables Devereau, who is unable to save himself before he is beheaded by an oncoming train. The chief radios Union Station in Chicago, Illinois, to report that a runaway train is coming, but a skeptical assistant controller delays efforts to avoid disaster. Meanwhile, George disconnects a rear car from the train, and he, Grover, Hilly and Ralston jump to safety on it. Warnings are broadcast throughout the station to evacuate, moments before the train crashes through the gate and into the lobby, while the car containing George, Hilly, Grover and Ralston rolls into the rail yard. As a crowd gathers around the wreckage, Grover steals a car in the lobby display and bids George and Hilly farewell. The couple leaves the station to find a park.