Heatherton was discovered by modeling scout Arri Taylor while vacationing with a friend on South Beach, Miami. At the age of 17, Heatherton moved to New York City and signed with the Marilyn Agency. She made her runway debut in September 2006 at the Diane von Fürstenberg fashion show. She has since walked the runway for Prada, Stella McCartney, Chanel, Tommy Hilfiger, Marc Jacobs, Jason Wu, Carolina Herrera, Michael Kors, Christian Lacroix, Lacoste, Valentino, Oscar de la Renta, Zac Posen, Dolce & Gabbana, Moschino, L.A.M.B., Elie Saab, Carmen Marc Valvo, Derek Lam, Etro and Isaac Mizrahi.

Heatherton began walking in the Victoria’s Secret Fashion Show in 2008. From 2010 to 2013, Heatherton was officially contracted as a Victoria’s Secret Angel. She appeared in several television commercials and advertising campaigns for the brand, including a billboard in New York City for the company’s “Showstopper” launch. She appeared in Victoria’s Secret’s “Very Sexy Now” fragrance’s spring 2015 advertising campaign. In 2013, it was announced that Heatherton had signed with IMG. She was ranked at number 35 on Askmen’s list of the “Top 99 Most Desirable” women for 2013. She appeared in Sports Illustrated Swimsuit Issues in 2015 and 2016. Also in 2016, she was featured in various campaigns for Adore Cosmetics.

Fashion stylist Clare Byrne sued Heatherton in 2017 for $10 million as compensation for a proposed sportswear line called RetroActive that never got off the ground.

In 2019, she signed with Select Model Management. After hiatus, she returned to modeling and appeared on the cover of Chicago Splash magazine in November 2019.