Barton was born in Hammersmith, London, England, to a Manchester-born English father and an Irish mother, but moved to New York City when she was five years old. She has two sisters, Hania and Zoe. Barton graduated from the Professional Children's School in Manhattan in 2004, and attended a summer school in Shakespearean acting at RADA in 2006.

As a child, Barton was a child fashion model. She was signed with Ford Models. Barton began her acting career at the age of nine in New York Theatre with a lead role in Slavs!, written by Tony Kushner. She took part in many plays, taking a lead role in James Lapine's Twelve Dreams. She made her film debut in Lawn Dogs, which won awards at film festivals around the world. Since then she has appeared in several films, including The Sixth Sense, Notting Hill, and Lost and Delirious, in which she starred.

Mischa Barton first appeared on television in 1996, as a younger Lily Montgomery in All My Children. Two years later she starred in the film Pups with Cameron Van Hoy. She also had a one-time appearance in the Fox show Fastlane, and appeared in the video for "Goodbye My Lover" by James Blunt. She has also appeared in Enrique Iglesias's video, Addicted. She played in eight episodes on the television show Once and Again as Katie Singer, Jessie Sammler's (Evan Rachel Wood)'s school friend.

Barton is best known for her role as Marissa Cooper in the TV series The O.C.. That role ended in a fatal car "accident" during the third season's finale, which aired on May 18, 2006. Though rumors had been swirling for weeks about the show's much hyped season finale death, Barton and NBC entertainment news program Access Hollywood infuriated fans of the show in revealing the character's death before the finale even aired.

In August 2006, news emerged that she may replace Teresa Palmer as Millie in Doug Liman's upcoming sci-fi thriller Jumper.