In 2000, Breckenridge guest starred as Shelly Weaver in Freaks and Geeks. When she was 15, she met James Franco at an audition. She was surprised that Franco recognized her on the set of Freaks and Geeks. She also guest starred in Buffy the Vampire Slayer, Charmed, CSI: Crime Scene Investigation, Dawson’s Creek, JAG, Medium, and Undeclared. Breckenridge also guest-starred as Francise in three episodes of Opposite Sex. In 2002, she appeared in the film Big Fat Liar, starring Frankie Muniz, as Jason Shepherd’s older sister Janie.

In 2006, Breckenridge starred as Monique in the film She’s the Man. She has also appeared in a couple of series that have later been canceled, such as the FX drama series Dirt from 2007 to 2008, in which she played Willa McPherson, a young upstart writer. In 2009, Breckenridge co-starred in the independent film The Bridge to Nowhere, directed by Blair Underwood. In 2012, she had a role in the film Ticket Out.

From 2015 to 2016, Breckenridge portrayed Jessie Anderson, a character from the comic book series of the same name, in season five and season six of the AMC post-apocalyptic horror series The Walking Dead. In 2015, she co-starred in the psychological thriller Dark from executive producer Joe Dante and director Nick Basile. In 2017, Breckenridge appeared in the recurring role of Sophie, Kate’s childhood friend and Kevin’s ex-wife, in the first season of the NBC drama series This Is Us. She was promoted to a series regular for the second season, and appeared in one episode in the third season and two episodes in the fourth season. Since 2019, Breckenridge has played lead character Melinda “Mel” Monroe in the Netflix series Virgin River.

In September 2015, Breckenridge married guitarist Casey Hooper. In September 2016, she gave birth to the couple’s first child, a son. In August 2017, she announced that they were expecting their second child; their daughter was born in December 2017.