Throughout the 1930s she starred in a number of plays, frequently collaborating with friend and actor-director-playwright Joshua Logan. Natwick made her film debut in John Ford's The Long Voyage Home as a cockney prostitute, and she movingly portrayed the landlady, an important character in 1945s "The Enchanted Cottage." However, she did not pursue a Hollywood career in earnest until the mid-1940s. Even after establishing her film career, Natwick could still frequently be seen in stage productions. She was twice nominated for Tony Awards: in 1957 for The Waltz of the Toreadors, and, in 1972 for the musical, 70 Girls 70.
Natwick made her name in small but memorable roles in several of John Ford classics, including 3 Godfathers (1948), She Wore a Yellow Ribbon (1948), and The Quiet Man (1952), as the sheltered widow Mrs. Tillane. The character actress was often given one-scene parts or shallow roles which she transcended with her personality and talent, such as her role as a birth control advocate in the comedy Cheaper by the Dozen (1950), the "well-preserved woman" in Alfred Hitchcock's The Trouble with Harry, and a sorceress in The Court Jester.
After leaving film in favor of stage and television in the mid-1950s, she returned with Barefoot in the Park as Jane Fonda's mother. The role earned Natwick her first and only Academy Award nomination. For much of the following decade, Natwick appeared exclusively in television, winning an Emmy Award for her role in the limited series The Snoop Sisters, a mystery which paired her with fellow film veteran Helen Hayes, and is fondly remembered as the rather British "Nanny" in Eloise. She also had a prominent guest appearance in the first season of Family, playing a grandmother who makes a final visit to her family to prepare them for her death. Her final role was in the 1988 film Dangerous Liaisons. Natwick died of cancer at age 89 in New York City.