An advertising executive from Manhattan, Roger Thornhill, finds himself abruptly plunged into a world of espionage and mistaken identity. While dining at a hotel, two henchmen misinterpret Thornhill for a government agent named George Kaplan. He is kidnapped and brought to a luxurious estate where he meets Phillip Vandamm, a spy who interrogates him. Thornhill denies being Kaplan but his captors remain unconvinced. He narrowly escapes a staged drunk-driving death and returns to his old life, only to find the police disbelieving his incredible story and suspecting him of murder. Thornhill becomes a man on the run, determined to clear his name and to solve the mystery of the nonexistent Kaplan.

Evading capture, Thornhill embarks on a cross-country journey to track down the real Kaplan. His quest leads him to Eve Kendall, a poised and enigmatic young woman on a train to Chicago. As they grow closer and he confides in her, she aids him but her loyalties remain unclear. Thornhill continues chasing elusive answers, transforming from advertising executive to unexpected hero. He finds himself in perilous situations, including an iconic chase through a cornfield, where a biplane relentlessly attacks him. Throughout this high-stakes game of cat and mouse, the deeper Thornhill delves into the world of espionage, the more dangerous his predicament becomes.