The series was cancelled by The CW in February 2008 due to low ratings, partly attributed to the 2007–08 Writers Guild of America strike, and no proper series finale was produced.

A retrospective episode was in development to conclude the series and give it closure, but it was scrapped after The CW offered the actors only half of their usual episodic salary, which the cast collectively refused.

After moving to The CW, the show's ratings plummeted when it was shifted to Sunday nights, prompting the network to move it back to its original Monday timeslot along with other black-aimed programs.

Jill Marie Jones, who played Toni Childs-Garrett, left the main cast after Season 6, though the character continued to appear.

The role of Darnell Wilkes was originated by Flex Alexander in Season 1 before being recast with Khalil Kain, who played the character as a recurring role in Seasons 2–5 and then as a main cast member from Season 6 onward.

Monica Charles Brooks, played by Keesha Sharp, appeared as a recurring character from Seasons 3–6 before being promoted to the main cast for Seasons 7–8.

The 2006 episode 'The Game' served as a backdoor pilot for the spin-off series The Game, guest-starring Tia Mowry as Joan's cousin Melanie Barnett; the spin-off was later revived by BET and eventually rebooted again for Paramount+ in 2021 as a direct sequel set in Las Vegas.

The entire Girlfriends series began streaming on Netflix on September 11, 2020, timed to commemorate the show's 20th anniversary.