An unaired pilot episode was filmed with two different actresses portraying main characters. Leslie Silva and Christina Cox played Toni Childs and Lynn Searcy, respectively. Clips from the original pilot could be seen during commercials advertising the 2000-2001 lineup of shows to air on UPN Monday nights. By the time the show premiered, however, Jill Marie Jones had replaced Leslie Silva as Toni, Persia White had replaced Christina Cox as Lynn, and the original pilot never aired.
The show was cancelled prematurely due to the 2007-2008 writers' strike. Once the strike ended, CW chose not to extend the series. This left fans with several cliffhangers for each of the main characters.
Tracee Ellis Ross is the only cast member to appear in every episode of the series.
Girlfriends was one of the highest rated scripted shows on television among African-American adults 18-34, including its spinoff, The Game (2006).
In July 2020, Netflix acquired the rights to six classic comedies led by Black actors, including Girlfriends. Netflix arranged the premiere of the show on its 20th anniversary: 13 September 2020.