She worked extensively in television, coming to prominence as Detective Janice Licalsi in the ABC police drama series NYPD Blue (1993–1994).

She is also known for her recurring role as Faye Moskowitz on Frasier and has starred in various films, including Heat (1995), Fear (1996), Daylight (1996), Things You Can Tell Just by Looking at Her (2000), Nine Lives (2005), and The Jane Austen Book Club (2007).

The next year she was cast in her first major role as mob-connected uniformed officer Janice Licalsi on the ABC police drama series, NYPD Blue.

The show's concept was based on the real-life experiences of her mother, Frederica Brenneman, as a superior court judge in the state of Connecticut.

Frederica Brenneman was one of Harvard Law School's first female graduates and became a juvenile court judge in Connecticut when Amy was three years old.

In 2007, Brenneman played the role of Sylvia Avila in The Jane Austen Book Club based on 2004 novel of the same name by Karen Joy Fowler.

She later starred in films The Face of Love and Words and Pictures, and was cast in HBO drama series The Leftovers opposite Justin Theroux.

"[26] In the February 28, 2007, all-star benefit reading of The Gift of Peace at UCLA's Freud Playhouse, she portrays an entrepreneur, alongside actors Ed Asner, Barbara Bain, George Coe, Wendie Malick, and James Pickens, Jr.

The play was an open appeal and fundraiser for passage of U.S. House Resolution 808, which sought to establish a Cabinet-level "Department of Peace" in the United States government, funded by a two percent diversion of The Pentagon's annual budget.

[27] In July 2008, Brenneman was nominated as a candidate on the Unite for Strength slate for a place on the national governing board of the Screen Actors Guild (SAG) in elections scheduled for September 18, 2008.