Sara Rue was born Sara Schlackman in New York City, New York, the daughter of Joan (née Rue), a municipal employee and former actress, and Marc Schlackman, a stage manager. The elder of two daughters, she was raised in New York, where her parents were active in Broadway theaters. She began her own acting career at the age of nine, appearing in the 1988 film Rocket Gibraltar as Kevin Spacey's daughter (and as the late Burt Lancaster's granddaughter). She also played a young Roseanne in the first meeting of Roseanne and Dan at a dance on the TV show Roseanne.

Rue won critical acclaim for her television series debut, starring in the comedy Grand, before going on to work on Phenom, Minor Adjustments, Zoe, Duncan, Jack & Jane, ER, The Division and Popular.

She has appeared in several films (A Map of the World, Can't Hardly Wait, A Slipping Down Life, Gypsy 83 and had a bit part as a babysitter in Gore Verbinski's adaptation of The Ring), and so impressed director Michael Bay that a role was written into the movie Pearl Harbor for her. Rue briefly appeared in the 2006 Mike Judge film Idiocracy, in the role of the Attorney General.

She currently stars in the stage musical Little Egypt with French Stewart, Jenny O'Hara, and Gregg Henry at The Matrix Theatre in Los Angeles.

Rue guest starred in Two and a Half Men as Berta's youngest daughter Naomi who is pregnant and, as the episode progresses, eventually has her baby on Charlie's couch. Rue is currently working on the movies Man Maid and For Christ's Sake, both of which are in post production.

Rue had a stint on the CBS sitcom The Big Bang Theory, playing the character of Leonard Hofstadter's girlfriend, Stephanie for 3 episodes. Her first appearance on the show occurred on November 17, 2008.

Rue will be producing an upcoming movie. The movie, written by Rue, will be a suspense thriller revolving around the world of online social networking. The yet to be titled film will be released through Dimension Films.