The film was shot in eight weeks, and required very few retakes. During the scene where James Stewart hiccups when drunk, you can see Cary Grant looking down and grinning. Since the hiccup wasn't scripted, Grant was on the verge of breaking out laughing and had to compose himself quickly. Stewart (apparently spontaneously) thought of hiccuping in the drunk scene, without telling Grant. When he began hiccuping, Grant turned to Stewart, saying, "Excuse me." The scene required only one take.
Cary Grant demanded top billing and $137,000 salary, a huge amount at the time (the equivalent of $2,860,325 in 2020 dollars.) As it turned out, however, he donated his entire earnings to the British War Relief Fund.
James Stewart never felt he deserved the Best Actor Oscar for his performance in this film, especially since he had initially felt miscast. He always maintained that Henry Fonda should have won instead for The Grapes of Wrath (1940), and that the award was probably "deferred payment for my work on Mr. Smith Goes to Washington (1939)."
Katharine Hepburn starred in the Broadway production of the play on which this film was based and owned the film rights to the material; they were purchased for her by billionaire Howard Hughes, then given to her as a gift.