Byington received a nomination for an Academy Award for Best Supporting Actress for her role as Penelope Sycamore in You Can't Take It with You (1938).

Her father died in 1891, and her mother sent her younger daughter to live with her grandparents in Port Hope, Ontario, while Spring remained with relatives in Denver.

However, since she was already of legal age, she decided to start her acting career in New York City, saying that she enjoyed it, and, "I can't do anything else very well.

Her daughters were living with friends J. Allen and Lois Babcock, in Leonardsville, New York, who were taking care of them while Byington worked in the city.

This connection landed her a role in her first Broadway performance in 1924, George S. Kaufman and Marc Connelly's Beggar on Horseback which ran for six months.

[8] In 1952, she joined CBS Radio to become the lead role of the widowed Lily Ruskin, in the sitcom December Bride.

From 1961 to 1963, Byington was cast as the wise, matronly housekeeper, Daisy Cooper, in the NBC Western series Laramie, starring John Smith and Robert Fuller.

On Laramie, Daisy serves as a surrogate grandmother to orphaned Mike Williams, played by the child actor Dennis Holmes.

She later appeared as Mrs. Jolly on Dennis Weaver's NBC comedy drama Kentucky Jones, and as wealthy J. Pauline Spaghetti in two episodes of Batman in 1966.

Byington spoke some Spanish, which she learned during the time spent with her husband in Buenos Aires; and she studied Brazilian Portuguese in her later years.

In July 1958, she confided to reporter Hazel Johnson that she had acquired a "small coffee plantation" in Brazil the month before and was learning Portuguese.

She surprised her co-stars in December Bride with her knowledge of the Earth's satellites and the constellations in the night sky,[3] and read The Magazine of Fantasy & Science Fiction.

[9] In August 1955, Byington began taking flying lessons in Glendale, California, but the studio made her stop because of insurance problems.

[3] In January 1957, she testified in the trial of the Sica brothers as a character witness on behalf of DaLonne Cooper, who was a "part-time script girl" for December Bride.