Gayheart began her career as a teen model in the 1980s, then advertising spokeswoman and subsequently appeared in a student short film by Brett Ratner, with whom she had an extensive relationship.

[8] Meanwhile, Gayheart earned a living appearing in commercials for Campbell's soup and Burger King, and also modeled for J. C. Penney catalogues.

[8] In 1993 and 1994, she had a recurring role in the Vanishing Son action series as cellist Clair Rutledge, the love interest of Russell Wong's main character, Jian-Wa Chang.

[13] The same year, she appeared onstage at Toronto's Canon Theatre in a production of The Last Night of Ballyhoo, opposite Rhea Perlman and Perrey Reeves.

[14] In 1999, Gayheart starred in the black comedy film Jawbreaker with Rose McGowan, Julie Benz, and Judy Greer as girls in an exclusive clique in their high school who inadvertently kill their friend.

[18] In 2002, Gayheart was hired for the role of Inara Serra on the television series Firefly but was fired after only one day of filming.

[21] David Rooney of Variety praised her performance, writing: "Exuding all the breezy confidence of a girl who's always been popular and pretty, Gayheart's Shelby provides a strong center, allowing only brief glimpses of the cracks in her cheerful, optimistic veneer and refusing to be treated as fragile goods by the clucking women around her.

The following year, she returned to Broadway in a revival of the comedy Boeing-Boeing opposite Christine Baranski, Mark Rylance, Greg Germann, Paige Davis, and Missi Pyle.

Gayheart returned to film in 2013, reuniting with Jawbreaker director Darren Stein for his comedy G.B.F., portraying the mother of a gay teenage boy.

[25] In 2019, Gayheart returned to film with a minor supporting role in Quentin Tarantino's Once Upon a Time in Hollywood, playing Billie Booth, the wife of Brad Pitt's character.

[26] Gayheart met Brett Ratner at age 15 on the day she moved to New York City in 1986, and the two carried on a romantic relationship that spanned 13 years.

"[30] On August 17, 2009, a nude video was posted on the website gawker.com that showed former Miss Teen USA contestant Kari Ann Peniche with Gayheart and husband Eric Dane.

"[36] On June 13, 2001, while driving a vehicle owned by Italian actor Marco Leonardi (her From Dusk Till Dawn 3 co-star), Gayheart struck nine-year-old Jorge Cruz Jr. as he walked across a street in Los Angeles.