Goldenhersh was born on March 26, 1973 in Chicago, Illinois and grew up in St. Louis. She has said that she is "half-Jewish by adoption on my father's side and Greek Orthodox on my mother's side". She was a fundamentalist Christian for several years, but ultimately drifted away from the faith in her mid-20s.

A graduate of Juilliard, Goldenhersh made her film debut in 1996 with her role in an adaptation of Herb Gardner's I'm Not Rappaport. From then on she appeared in films such as Swallowed, The Great Gatsby and The Believer. Goldenhersh also appeared on television in Sex and the City and episodes of the Law & Order franchise. She then focused on her stage career; her 2005 Broadway debut was in Doubt, opposite Cherry Jones and Brian F. O'Byrne.

Goldenhersh was nominated for a Tony Award in 2005 for "Best Performance by a Featured Actress in a Play" for her role as Sister James in Doubt. She also won a Theatre World Award for that performance.

In 2006, Goldenhersh auditioned for the show The Class, a sitcom created by David Crane (one of the creators of Friends), and Jeffrey Klarik (an executive Producer of "Mad About You") and was cast in the part of Lina Warbler. The Class premiered in September 2006 and won a People's Choice Award for "Best New Comedy" in January 2007. The series wasn't renewed for a second season.