Smith was born Lois Arlene Humbert in Topeka, Kansas, the daughter of Carrie Davis (née Gottshalk) and William Oren Humbert, who was a telephone company employee. She is a graduate of the University of Washington. She studied acting in New York City at Lee Strasburg's Actor's Studio, famous for producing many "method" actors.
After two TV appearances, Smith made her film debut in East of Eden in 1955. Additional film credits include Five Easy Pieces, Up the Sandbox, Four Friends, Fatal Attraction, Fried Green Tomatoes, How to Make an American Quilt, Hard Promises, Dead Man Walking, Twister, Minority Report, Tumbleweeds, Hollywoodland and Sweet Land. 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, One Life to Live) and numerous primetime dramas, including The Defenders, Dr. Kildare, Route 66, thirtysomething, The Practice, Law & Order, Law & Order: Special Victims Unit, Law & Order: Criminal Intent, Grey's Anatomy, Cold Case and True Blood.
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.