Smith began her career as a teenage model. She moved to Los Angeles and planned to appear in commercials to pay for her studies at the University of California. She appeared in an HBO commercial during the Super Bowl, through which an agent found her and suggested she try her hand at acting.

In 1996, Smith played the ex-girlfriend of the protagonist in the film Jerry Maguire. She is best known for the role of Mary Winchester in the television series Supernatural. She also played the role of Sarah Lennox, the wife of Captain William Lennox (Josh Duhamel) in the film Transformers. Smith has appeared in a large number of television series, including Rizzoli & Isles and Criminal Minds.