His first film as a director was A Man to Remember (1938), which The New York Times considered one of the ten best films of 1938. Kanin is best remembered, however, for his collaborations with his wife, actress Ruth Gordon, whom he married in 1942. Together, they wrote the Spencer Tracy/Katharine Hepburn film comedies Adam's Rib (1949) and Pat and Mike (1952), both directed by George Cukor.

His 1946 play Born Yesterday, which he also directed, ran for 1,642 performances. Kanin worked, uncredited, on the screenplay of the 1950 film adaptation.His other stage work includes directing The Diary of Anne Frank (1955), which ran for 717 performances, and the musical Funny Girl (1964), which ran for 1,348 performances.

In 1990, Kanin, a widower since 1985, married the actress Marian Seldes, who survives him. In 1999, Kanin died at age 86 in New York City of undisclosed causes.

He was a colleague of Thornton Wilder, who mentored him, and an admirer of the work of Frank Capra. Kanin said "I'd rather be Capra than God, if there is a Capra." Kanin and Katharine Hepburn were the only witnesses to Laurence Olivier and Vivien Leigh's wedding in California on August 31, 1940. In 1941, he and Katharine Hepburn worked with his brother Michael Kanin and Ring Lardner, Jr., on the early drafts of what would become Woman of the Year, right before Garson enlisted in the Army. He is also quoted as saying, "When your work speaks for itself, don't interrupt."