She made her professional debut on the New York stage, appearing in Beside Herself alongside Melissa Joan Hart, at the Circle Repertory Theatre.Two years later, Flockhart appeared in the television movie Darrow.
Flockhart also starred in the Off-Broadway production of Ensler's The Vagina Monologues.
In 2004, Flockhart appeared as Matthew Broderick's deranged girlfriend in The Last Shot.
She earned a Golden Globe Award for the role in 1998.
Flockhart also appeared on the June 29, 1998, cover of Time magazine, Flockhart performed in a starring role as Kitty Walker, opposite Sally Field, Rachel Griffiths and Matthew Rhys, in the ABC critically acclaimed prime time series Brothers & Sisters, which premiered in September 2006 in the time slot after Desperate Housewives.
In 2014, Flockhart landed a role in Full Circle's second season, as mob boss Ellen. This had been Flockhart's first acting role in three years, after her hiatus when Brothers & Sisters ended.
In 2015, Flockhart was cast in the television series Supergirl as Cat Grant, a "self-made media magnate and founder of Cat Co" and boss to Kara (Supergirl's alter ego).The show was cancelled in May 2011 after running for five years.Flockhart's character was significant throughout the series' first four years, but her appearances were reduced for the 2010–2011 season, coinciding with the departure of TV husband Rob Lowe.Rutgers inducted her into the Hall of Distinguished Alumni on May 3, 2003.Flockhart moved to New York City in 1989 and began seeking auditions, living with three other women in a two-bedroom apartment and working as a waitress and aerobics instructor. In spring 1989, Flockhart made her first television appearance in a minor role in an episode of Guiding Light as a babysitter.In 1996, Flockhart appeared as the daughter of Dianne Wiest and Gene Hackman's characters in The Birdcage.