Born Samuel Yewell Tompkins in Owensboro, Kentucky, Ewell began acting in Summer Stock in 1928 with Don Ameche, before moving to New York in 1931. He enrolled in the Actors Studio alongside classmates Montgomery Clift and Karl Malden. He made his Broadway debut in 1934 and his film debut in 1940, and for several years played comic supporting roles. He attracted attention with a strong performance in the film Adam's Rib (1949) and he began to receive Hollywood roles more frequently.

His most successful and arguably most identifiable role came in 1952 when he began the Broadway production of The Seven Year Itch. With Vanessa Brown as "The Girl", the show ran for almost three years, and Ewell played the part more than 750 times. He won a 1953 Tony Award for this role. He reprised his role in the 1955 film version, with Brown replaced by Marilyn Monroe. The scene of Ewell slyly admiring Monroe as she stood over a subway grate with her skirt billowing, has become one of the most iconic moments in films. He won a Golden Globe Award for his performance.

He enjoyed another film success in The Girl Can't Help It (1956) opposite Jayne Mansfield, but as his film and theater careers seemed to have reached their peaks, he turned his attention to television. Over several years he played guest roles in numerous series, and received an Emmy Award nomination for his continuing role in the television series Baretta, with Ewell commenting that working on that series had given him greater pleasure than any project he had ever worked on. His final acting performance was in a 1986 episode of Murder, She Wrote.

In a 1983 interview Ewell stated that the theater was the only arena in which actors could be creative, because films were the work of directors, and television was the work of technicians. He said he did not hold any particular regard for any of his films, with the exception of The Seven Year Itch. He also spoke highly of his co-star Monroe, saying that he "adored" her and that she was "such a lovely person to work with". He claimed never to have seen any of his films, including The Seven Year Itch, and had only ever seen glimpses of himself onscreen when his wife was watching television. He said he suffered from an inferiority complex and could not bear to see himself on screen as he was too critical of himself.

He died in Woodland Hills, California, aged 85, of undisclosed causes.