Elizabeth Anne Caplan was born and raised in Los Angeles, California. Caplan attended Alexander Hamilton High School, a public high school on Los Angeles's Westside, as a student at the school's prestigious Academy of Music, a performing arts program.
She decided to pursue drama after she lost interest in playing the piano. She starred in productions of Much Ado About Nothing and You Can't Take It with You.
Caplan began her television acting career in 1999 playing the minor role of Sara on the critically acclaimed series Freaks and Geeks, most memorably as a disco dancer in the episode "Discos and Dragons." Caplan had a series of guest appearances on numerous shows, and was a guest on The Sharon Osbourne Show. She also appeared in Jason Mraz's music video "You and I Both."
In 2001, she played freak of the week Tina Greer in an episode of Smallville, and reprised her role on the show in 2003. She appeared in two episodes of the ABC series Once and Again as Sarah, the ex-girlfriend of Mischa Barton's character, Katie Singer.
Although already an experienced actress, she gained notice in the 2004 movie Mean Girls, where she played the alternative-styled Janis Ian, named for the singer-songwriter. In 2003, she starred in the television series The Pitts, playing Faith Pitt. In the second season of Tru Calling, she played Avery Bishop, a friend of Tru Davies.
Caplan landed a starring role in 2005, playing Marjee Sorelli, the troubled sister in Related, a one-hour dramedy on The WB. The show was canceled after one season. In 2006, Caplan played the starring role of Sara Weller in Wesley Strick's thriller, Love is the Drug. She was named one of “10 Actors to Watch” that year by Daily Variety.
After Related ended, Caplan was cast in the CBS sitcom The Class, which premiered on September 18, 2006, and lasted one season. She played Kat Warbler, one of several elementary-school friends that reunite after 20 years.
Caplan, along with Jason Ritter, presented a People's Choice Award for Favorite Soundtrack From a Movie in January 2007. She appeared with her The Class co-star Heather Goldenhersh on the talk show The View in early 2007.
In 2008, Caplan appeared in the film Cloverfield playing Marlena Diamond, and was nominated for a Saturn award as Best Supporting Actress. She also appeared in the romantic comedy My Best Friend's Girl playing Ami, the roommate of Kate Hudson's character Alexis.
She is the voice of Faith Pitt in the animated version of The Pitts, released in 2009. In 2008, Caplan guest starred on the vampire-themed HBO show True Blood in a multiple-episode story arc as Amy Burley, the drug-addled girlfriend of Sookie Stackhouse's brother, Jason.
Caplan also appeared in the recently cancelled, yet critically acclaimed Starz ensemble comedy Party Down, playing a struggling comedienne who is part of a catering crew.
In 2010, she appeared in 127 Hours, a film directed by Danny Boyle. Based on a true story, Caplan played the sister of hiker Aron Ralston, played by James Franco, who was forced to amputate his own arm after being trapped by a boulder.
Caplan appeared in the new TV comedy New Girl starring Zooey Deschanel.