Leerhsen was born in Ossining, New York on Valentine's Day, where she was raised along with her two sisters, Nora and Debbie, by their father Charles Leerhsen, a long time editor of celebrity publication US Magazine (which became US Weekly in March 2000). She attended St. Augustine's School and Ossining High School (where she sang in the choir) and graduated from Boston University College of Fine Arts in 1998. She earned B.F.A (summa cum laude) in acting the same year.

After graduation, Leerhsen's first role was as Sarah in a 1999 short film Junior Creative, which received several good reviews. During its production, she got the lead role of a practicing witch in the controversial Horror sequel Book of Shadows: Blair Witch 2, though she originally auditioned for the part that eventually went to Kim Director. She went to the audition with short blonde hair, and, as director Joe Berlinger described it, "completely Gothed-out", but ultimately was given the role of Erica. It was Berlinger who decided to make her character a long-haired redhead.

Following Blair Witch 2, she appeared in the third season of The Sopranos, where she played a lesbian tennis instructor who falls for Drea de Matteo's character. She would also have part in the well-acclaimed TV show The Guardian, where her character got written out after several episodes. In the same year she had a supporting role in Woody Allen's Hollywood Ending.

Leerhsen was honored with the title "Arrow in the Head's Mistress of the Year 2003". That year saw the release of the very successful Horror remake The Texas Chainsaw Massacre, in which Leerhsen had a prominent role as one of the doomed teens. During her screen test for the film, her screams were so loud that people on other floors of the building called the police to report that a young woman was being attacked. The same year she returned to acting on television with a guest appearance on Alias, and then reunited with Woody Allen in his new film, Anything Else.

In 2004, Leerhsen starred in an independent Thriller The Warrior Class, where she played Anson Mount's love interest. The film got released on DVD on February 06, 2007. Months later, she started acting in theaters, and appeared in Woody Allen's A Second Hand Memory, which attracted attention from a wider adult audience and received good reviews.

A year later, Leerhsen starred along Michael Pena in an independently-made Toronto Film Festival-smash Little Athens, which got released on DVD on November 21, 2005. The same year she had a guest appearance on Jennifer Love Hewitt's television show Ghost Whisperer, and starred in Mozart and the Whale, which was released in limited theaters on April 14, 2006.

The year 2006 opened with Leerhsen's guest appearance on CSI: Miami. Shortly after she was landed a starring role in Wrong Turn 2: Dead End, the well-acclaimed 2007 sequel to the 2003 horror film Wrong Turn, where she did a lot of her own stunts. The sequel got released on DVD on October 09, 2007 in USA, and January 08, 2008 in UK.

Before filming Wrong Turn 2: Dead End, Leerhsen shot a Horror/Thriller Organizm, where she plays a hazmat specialist. The film will premiere on the Sci-Fi Channel on February 23, 2008.

In 2007, Leerhsen starred in an indie film Lonely Joe, which has been said to be a Supernatural Horror/Thriller "in the veins of Saw and The Sixth Sense", and has been slated for an unknown 2008 release. Her most recent project has been a horror film Slaughter, which has finished shooting in January of 2008, and is expected to be released sometime in late 2008.

Leerhsen enjoys running, playing basketball and Yoga. She currently lives in Los Angeles with her husband, and is good friends with actress Emily Deschanel, with whom she went to the same college.