Monaghan's first notable though minor parts were in episodes of Young Americans, (in which she appeared twice), and Law & Order: Special Victims Unit, both in 2001. Monaghan made her big screen debut that year in the small role of Henrietta in the movie Perfume. This was followed by another small role in Unfaithful in 2002. She expanded her résumé by doing commercials for products such as Stayfree deodorant in 2001 and Secret Sheer dry in 2002.

Monaghan had a big break in 2002 when she co-starred in the television series Boston Public in the role of Kimberly Woods. After guest starring for a season on the television series, Monaghan turned back to the silver screen. She appeared in It Runs in the Family in 2003, Winter Solstice in 2004 and Kiss Kiss Bang Bang in 2005, in which she did her first and so far only on-screen nude scene with co-star Robert Downey, Jr. She is also known for having scenes deleted from both Constantine and Syriana. Her audition tape from Constant