Struthers was born in Portland, Oregon; her maternal grandparents were Norwegian immigrants.

Struthers is perhaps best known for her portrayal of Archie Bunker's daughter, Gloria Bunker Stivic, on the popular and groundbreaking 1970s sitcom All in the Family. After a shaky start, word of mouth propelled the program to the top of the Nielsen Ratings heap, giving tens of millions of viewers the chance to see "Gloria" pontificating her ultra-liberal viewpoints about negative stereotypes and inequality.

In Five Easy Pieces (1970) she had a memorable sex scene with Jack Nicholson.

In an appearance on The Mike Douglas Show in 1975 she showed the host and audience a piece of flesh-colored rubber that she was wearing in her TV movie, Hey, I'm Alive!, based on the true story of a young woman stranded in a snow bank. She explained that it was a make-up appliance to expand her nose, because she was portraying a Jewish girl.

She has acted in television series, including being a regular performer on The Smothers Brothers Comedy Hour and playing the titular role in the short-lived All in the Family spin-off Gloria (1982-1983), on stage, and in made-for-TV movies and feature films. She also has a recurring role as Bill Miller's mother, Louise, on the CBS sitcom Still Standing.

Since 2000, Struthers has regularly appeared on the dramedy Gilmore Girls as the girls' neighbor Babette Dell.

She has also provided voices for a number of animated series such as TaleSpin (as Rebecca Cunningham), and Dinosaurs (as Charlene Sinclair).

Struthers has been a long-time spokeswoman for the Christian Children's Fund, advocating on behalf of impoverished children in developing countries.

Struthers married William Rader on December 18, 1977. Now divorced, they had one child together.