- Cary Grant as T. R. Devlin
- Ingrid Bergman as Alicia Huberman
- Claude Rains as Alexander Sebastian
- Leopoldine Konstantin as Madame Anna Sebastian
- Louis Calhern as Captain Paul Prescott, an officer of the US Secret Service
- Moroni Olsen as Walter Beardsley, another Secret Service officer
- Ricardo Costa as Dr. Julio Barbosa
- Reinhold Schünzel as Dr. Anderson, a Nazi conspirator
- Ivan Triesault as Eric Mathis, a Nazi conspirator
- Eberhard Krumschmidt as Emil Hupka, a Nazi conspirator
- Alexis Minotis (billed as Alex Minotis) as Joseph, Sebastian's butler
- Wally Brown as Mr. Hopkins
- Sir Charles Mendl as Commodore
- Fay Baker as Ethel
Biographer Patrick McGilligan writes that "Hitchcock rarely managed to pull together a dream cast for any of his 1940s films, but Notorious was a glorious exception." Indeed, with a story of smuggled uranium as a backdrop, "[t]he romantic pairing of Grant and Bergman promised a box office bang comparable to an atomic blast."
Not everyone saw it that way, however, most notably the project's original producer David O. Selznick. After he sold the property to RKO to raise some quick cash, Selznick lobbied hard to get Grant replaced with Joseph Cotten; the United States had just dropped atomic bombs on Japan and Selznick argued that the first film out about atomic weaponry would be the most successful—and Grant was not available for three months. Unsaid was that Selznick was leery of Grant because he "would come with ego and salary demands," but most telling of all—Selznick owned Cotten's contract. Hitchcock and RKO production executive William Dozier invoked a clause in the project sale contract, blocked Selznick's attempts, and Grant was signed to play opposite Bergman by late August 1945.
Hitchcock "had oddly wanted the epicene Clifton Webb" to play Alexander Sebastian. Selznick pressed for Claude Rains in typical Selznick memo-heavy style: "Rains offers 'an opportunity to build the gross of Notorious enormously... .[D]o not lose a day trying to get the Rains' deal nailed down.'" Whether they were thinking in Selznick's box office terms or in more artistic ones, Dozier and Hitchcock agreed, and Rains' performance transformed Sebastian into a classic Hitchcock villain: sympathetic, nuanced, in some ways as admirable as the protagonist.
The final major casting decision was Mme. Sebastian, Alex's mother. "The spidery, tyrannical Nazi matron demanded a stronger, older presence," and when attempts to obtain Ethel Barrymore and Mildred Natwick fell through, German actor Reinhold Schünzel suggested Leopoldine Konstantin to Hitchcock and Dozier. Konstantin had been one of pre-war Germany's greatest actresses. Notorious was Konstantin's only American film appearance and "one of the unforgettable portraits in Hitchcock's films."
Alfred Hitchcock's cameo appearance, a signature occurrence in his films, takes place at the party in Sebastian's mansion. At 1:04:43 (1:01:50 on European DVDs and 64:28 of the edited cut) into the film, Hitchcock is seen drinking a glass of champagne as Grant and Bergman approach. He sets his glass down and quickly departs.