Natwick began performing on the stage at age 21 with “The Vagabonds”, a non-professional theatre group in Baltimore. She soon joined the University Players on Cape Cod. Natwick made her Broadway debut in 1932 playing Mrs. Noble in Frank McGrath’s play Carry Nation, about the famous temperance crusader Carrie Nation. Throughout the 1930s she starred in a number of plays, frequently collaborating with friend and actor-director-playwright Joshua Logan. On Broadway, she played “Prossy” in Katharine Cornell’s production of Candida. She made her film debut in John Ford’s The Long Voyage Home as a Cockney slattern, and portrayed the landlady in The Enchanted Cottage (1945).

She continued to appear onstage, and made regular guest appearances in television series. She was twice nominated for Tony Awards: in 1957 for The Waltz of the Toreadors, the same year she also starred in Tammy and the Bachelor with Debbie Reynolds and Leslie Nielsen and in 1972 for the musical 70 Girls 70. She returned to film in Barefoot in the Park (1967) as the mother of the character played by Jane Fonda. The role earned Natwick her only Academy Award nomination for Best Supporting actress. One of Natwick’s memorable roles was in The House Without a Christmas Tree (1972), which starred Jason Robards and Lisa Lucas. The program’s success spawned three sequels: The Thanksgiving Treasure, The Easter Promise, and Addie and The King of Hearts.

In 1971, Natwick co-starred with Helen Hayes in the ABC Movie of the Week, Do Not Fold, Spindle, or Mutilate, in which their characters worked together as amateur sleuths. The success of that telefilm resulted in a similar team-up the next year, portraying two mystery-writing and solving sisters; this spawned the 1973-74 series The Snoop Sisters, which was part of The NBC Wednesday Mystery Movie. For her performance, Natwick won the Primetime Emmy Award for Outstanding Lead Actress in a Miniseries or a Movie. In 1981, Natwick joined Hayes as the first members of the Board of Advisors to the Riverside Shakespeare Company. Both attended and supported several fund raisers for that off-Broadway theatre company.

On October 25, 1994, Natwick died of cancer at her home in Manhattan at age 89. She is interred at Lorraine Park Cemetery in Baltimore.