At a New York City hotel bar in 1958, two thugs, looking for someone they refer to as “George Kaplan”, see a waiter who is calling his name. Advertising executive Roger Thornhill summons the same waiter and Thornhill is, apparently for that reason, mistaken for Kaplan, kidnapped, brought to the Long Island estate of Lester Townsend and interrogated by spy Phillip Vandamm. Despite Thornhill’s denials, Vandamm thinks he is lying and has henchman Leonard arrange Thornhill’s death, in a staged drunken driving accident. Thornhill, surviving, is arrested for driving under the influence and taken to the Glen Cove, New York police station.
Thornhill fails to convince his mother and the police of what happened. Journeying to the scene of the crime with police, a woman at Townsend’s home says he showed up drunk at her dinner party. She also claims that Townsend is a United Nations diplomat. While searching a hotel room with his mother that appears to belong to Kaplan, Thornhill answers a phone call from thugs who are in the lobby. He escapes and visits the U.N. General Assembly building to meet Townsend but realizes this person is not the man he met on Long Island. As he questions Townsend, one of the thugs throws a knife, killing Townsend. Thornhill catches Townsend as he falls and grabs the knife, which gives the appearance that he was the murderer. A nearby photographer captures this apparent crime; Thornhill flees and attempts to find the real Kaplan.
A government intelligence agency realizes that Thornhill has been mistaken for Kaplan, an imagined persona created by the agency to thwart Vandamm; they decide against rescuing him for fear of compromising their operation.
Thornhill sneaks onto a train, the 20th Century Limited. On the train, he meets Eve Kendall, who hides him from the police; the two establish a relationship—on her part because she is secretly working with Vandamm. In Chicago, she tells Thornhill she arranged a meeting with Kaplan at an isolated bus stop in a rural area. Thornhill waits there, but rather than Kaplan arriving, Thornhill is attacked by a crop duster plane. After trying to hide in the fields, he steps in front of a speeding tank truck; it brakes for him and the airplane crashes into it, allowing him to escape.
Thornhill reaches Kaplan’s hotel in Chicago to discover that Kaplan had already checked out and left before the time when Kendall claimed she talked to him on the phone. When Thornhill goes to her room and confronts her, she leaves; he tracks her to an art auction where he finds Vandamm. Vandamm, who is purchasing a Mexican Purépecha statue, leaves his thugs to deal with Thornhill. Thornhill, in order to escape, disrupts the auction and police are summoned, who take him away. He explains that he is the fugitive murderer and they release him to the government agency’s chief, “The Professor”; who reveals that Kaplan was invented to distract Vandamm from the real government agent—who is Eve Kendall. Thornhill agrees to help maintain her cover.
At the Mount Rushmore visitor center, Thornhill—now willingly playing the role of Kaplan—negotiates Vandamm’s turnover of Kendall for her prosecution as a spy. When Thornhill appears to confront Kendall, she shoots him, seemingly fatally, with a handgun that is actually loaded with blanks and flees.
Afterward, the Professor arranges for Thornhill and Kendall to meet. Thornhill discovers Kendall must depart with Vandamm and Leonard on a plane. When Thornhill tries to dissuade her from going, he is knocked unconscious and locked in a hospital room. Thornhill escapes the Professor’s custody and goes to Vandamm’s house to rescue Kendall.
At the house, Thornhill overhears that the sculpture holds microfilm and that Leonard discovered that the gun used by Kendall to kill Thornhill was filled with blanks. Vandamm indicates that he will kill Kendall during the flight. Thornhill warns her with a surreptitious note. Vandamm, Leonard and Kendall depart the house to board the plane. As Vandamm boards the plane, Kendall takes the sculpture and runs to the pursuing Thornhill. They flee to the top of Mount Rushmore. As they climb down the mountain they are pursued by Vandamm’s thugs, including Leonard, who is fatally shot by a park ranger. Vandamm is taken into custody by the Professor.
Kendall meanwhile is hanging on by her fingertips on the mountain. Thornhill reaches down to pull her up, at which point the scene cuts to him pulling her—now the new Mrs. Thornhill—into the upper berth of a train. The train then enters a tunnel.