Advertising executive Roger Thornhill (Cary Grant) is mistaken for "George Kaplan". Kidnapped by two thugs, he is brought to the Long Island estate of Lester Townsend, and interrogated by spy Phillip Vandamm (James Mason). Vandamm's henchman Leonard (Martin Landau) tries to arrange Thornhill's death, but he manages to escape a staged drunken driving accident.
Thornhill fails to convince his mother and the police that he was kidnapped. A woman at Townsend's home (Josephine Hutchinson) says he got drunk at her dinner party. She says Townsend is a United Nations diplomat. Thornhill searches Kaplan's hotel room, and visits the U.N. General Assembly building. He discovers that Townsend (Philip Ober) is not the man he met on Long Island. Townsend is killed instead of Thornhill, who is then wanted for murder. Thornhill flees and attempts to find the real Kaplan.
Thornhill sneaks onto the 20th Century Limited. He meets Eve Kendall (Eva Marie Saint), who protects him from the police and sleeps with him. Kendall is actually working with Vandamm and his thugs. In Chicago, Kendall tells Thornhill she has arranged a meeting with Kaplan at an isolated bus stop.
Thornhill waits, but no one comes. He is nearly assassinated by a crop duster plane. He steps in front of a speeding tank truck; the airplane crashes into the truck, and Thornhill escapes.
When he reaches Kaplan's hotel in Chicago, he discovers that Kaplan had checked out and left before Kendall said she talked to him on the phone. Thornhill goes to her room, but she leaves. He tracks her to an art auction, where he finds Vandamm and his thugs. Vandamm purchases a Mexican Purépecha statue and departs. Thornhill is trapped, but acts crazy so the police come and take him away. He tells them he is the fugitive murderer; the police release him to FBI chief Professor (Leo G. Carroll), who reveals that Kaplan does not exist, and was invented to distract Vandamm from the real government agent: Kendall. Thornhill agrees to help maintain her cover.
At the Mount Rushmore visitor center, Thornhill (as Kaplan) negotiates Vandamm's turnover of Kendall for her prosecution as a spy. "Kaplan" confronts Kendall; she shoots him "fatally" with a handgun (loaded with blanks), and flees. Thornhill and Kendall meet in a forest. Thornhill discovers Kendall must depart with Vandamm and Leonard on a plane. Thornhill evades the Professor's custody, and goes to Vandamm's house to rescue Kendall.
At the house, Thornhill overhears that the sculpture holds microfilm. Vandamm implies that he will kill Kendall during the flight. Thornhill lets Kendall know they plan to kill her, but he is captured. As Vandamm is boarding the plane, Kendall takes the sculpture and runs to Thornhill. They attempt to flee, but they realize they are on top of Mount Rushmore. They begin to climb down the mountain's sculpture, pursued by two thugs. After a harrowing chase, all turns out well for them.
Later, Thornhill invites Kendall, as the new Mrs. Thornhill, onto the upper berth of a train, which then enters a tunnel.