Born in Topeka, Kansas, Smith is a graduate of the University of Washington. She made her film debut in East of Eden in 1955. Additional film credits include Five Easy Pieces, Up the Sandbox, Fatal Attraction, Fried Green Tomatoes, How to Make an American Quilt, Dead Man Walking, Twister, Minority Report, Tumbleweeds, and Hollywoodland.

Much of Smith's career has been spent in television, appearing in early anthology series (Studio One, Robert Montgomery Presents), soap operas (Another World, Somerset, The Edge of Night, All My Children), and numerous primetime dramas, including The Defenders, Dr. Kildare, Route 66, thirtysomething, The Practice, Law and Order, Law & Order: Special Victims Unit, Law & Order: Criminal Intent, and Grey's Anatomy.

Smith made her Broadway debut in the 1952 comedy Time Out for Ginger. A member of the Steppenwolf Theatre Company, she appeared as Ma Joad in their production of The Grapes of Wrath in Chicago, San Diego, and London before bringing it to New York City, where her performance earned her a Tony Award nomination.

Smith presently lives on the Upper West Side of Manhattan.