A former host of MTV's Total Request Live, she portrayed Peyton Sawyer on The WB/The CW drama One Tree Hill for six seasons (2003–2009).

Burton was a co-host on the Drama Queens podcast along with her former One Tree Hill co-stars, Sophia Bush and Bethany Joy Lenz until the summer of 2024.

In October 2017, when news of the Harvey Weinstein sexual abuse cases broke, Burton retweeted a 2003 video clip from TRL Uncensored in which Ben Affleck squeezed her breast on air.

'"[14] In 2021, Burton started a podcast with One Tree Hill co-stars Sophia Bush and Bethany Joy Lenz titled Drama Queens.

Burton was cast in The WB drama series One Tree Hill as Peyton Sawyer, an independent visual and musical artist and cheerleader, in April 2003.

While still a One Tree Hill cast member, Burton made her feature film debut opposite Allison Janney and Cheryl Hines in the 2005 well-reviewed drama Our Very Own which centered on five small-town teenagers who dream of a better life.

[18][19][20] In 2008, Burton appeared in both the Fox Searchlight Pictures drama The Secret Life of Bees, as the deceased mother of Dakota Fanning's character, and the limited release thriller The List.

Burton was next cast in the film Bloodworth opposite Hilary Duff and Val Kilmer, an adaptation of the novel Provinces of Night by William Gay.

Burton won a recurring arc in the USA Network crime drama series White Collar in 2010 as Sara Ellis, an insurance investigator in the second season.

[21] 2012 saw Burton guest-starring on the ABC police comedy-drama Castle (season 4, episode 13) as a reality television star who is accused of murder.

[22] Next came a recurring role in the ABC medical drama Grey's Anatomy for the final three episodes of the 2013 ninth season, as Dr. Lauren Boswell.

[23] Burton reunited with One Tree Hill co-star Tyler Hilton for a recurring role on CBS sci-fi drama Extant in 2015.

On May 5, 2020, Burton published her first non-fiction book, The Rural Diaries: Love, Livestock, and Big Life Lessons Down on Mischief Farm.

Burton has been candid on social media about the couple's struggle to conceive, stating that it took five years to successfully carry a second baby to term.

[34] Subsequently, she has spoken out publicly in support of abortion rights after the Supreme Court decision on Dobbs v. Jackson Women's Health Organization that overturned Roe v. Wade, stating:[35]This is my child.