Her early work included television guest roles on ER, Sports Night, The Adventures of Brisco County, Jr., and Murder, She Wrote.

Starting in 1999, Moloney had a main role on The West Wing as Donna Moss, beginning as an assistant to Deputy White House Chief of Staff Josh Lyman (Bradley Whitford) before pursuing further ambitions in the next election.

[8] In 2007, Moloney played Dana Chase, who has a relationship with Tommy Caffee (Jason Clarke) in six episodes of the second season of Brotherhood.

In 2009, she appeared in the American series Life on Mars as Professor Pat Olsen in the episode "Revenge of the Broken Jaw".

In 2007, Moloney made her Off-Broadway stage debut as Theresa in the Playwrights Horizons production 100 Saints You Should Know, written by Kate Fodor and directed by Ethan McSweeny.