When Morena Baccarin was 10, she moved with her family to Greenwich Village, New York. She later attended the Fiorello H. LaGuardia High School of Music & Art and Performing Arts (the Fame high school) before she entered the theater program at Juilliard, where Wes Bentley was a classmate.

Morena landed her first movie role in the improvised fashion world comedy Perfume (2001). This was followed by a lead role in the film festival hit, Way Off Broadway (2001). Shortly before moving to Los Angeles, Morena appeared with Natalie Portman and understudied for her role in the acclaimed Central Park production of The Seagull. Firefly was her first television show. Morena reprised her role from Firefly in the film Serenity (2005) and also provided the voice for Black Canary in multiple episodes of the animated series Justice League Unlimited in 2005.