Leigh started acting at an early age and debuted in the film world at age 15 in 1997's Kickboxing Academy. In 2001, Leigh had the lead role in the film Not Another Teen Movie as Janey Briggs. She also appeared in Marilyn Manson's music video "Tainted Love", a song which appeared in the film. She was ranked #65 on the Maxim Hot 100 Women of 2002.
In 2002, Leigh was cast in two short-lived TV series: Girls Club, in which she played lawyer Sarah Mickle, and That '80s Show, in which she played punk rocker June Tuesday. She then became a series regular on the ABC legal drama The Practice, but was let go at the end of the season due to budget cuts. Following that, she joined the cast of Reunion in September, 2005. In ABC's Grey's Anatomy, Leigh first appeared as a woman in Joe's bar who tried to pick up Derek Shepherd. In the third season finale, it was revealed that she was Lexie Grey, Meredith's half-sister. She was made an official series regular for season four.
On July 20, 2002, she married actor Nathan West and together they have two children. Their son, Noah Wilde, was born in December 2003. She gave birth to her second child, a daughter named Taelyn, in September 2006. Leigh and West worked side-by-side in 2000 on the television series 7th Heaven playing Mary Camden's troubled friends, Frankie and Johnnie. On December 28, 2008 it was announced that Chyler and her husband were expecting their third child.