The series originally aired on ABC as part of its TGIF comedy lineup from April 1994 to April 1995, but was cancelled by ABC in 1995.

After ABC cancelled the show, The WB picked it up in 1995 as a replacement for the series Muscle on its Wednesday night lineup, and it ran for four more seasons until 1999.

Brittany Murphy appeared in the first season as the character Sarah before leaving the show to star in Clueless.

For the first five seasons, Tia and Tamera regularly broke the fourth wall, talking directly to the camera and the viewer, a device that was later dropped.

The original theme song was written and composed by Tim Heintz, Randy Petersen and Kevin Quinn and performed by Carmen Carter, while seasons five and six featured a remix with vocals performed by Tia and Tamera Mowry themselves.

The show's DVD releases from 2016 and 2017 were heavily edited due to music copyright issues.

A revival of Sister, Sister was confirmed to be in development in 2018, with star Jackée Harry stating on the talk show Steve that 'it's happening', but the project was put on hold indefinitely in 2019 due to a lack of interest and copyright issues.

George Spiro Dibie won an Emmy Award in 1995 for Outstanding Individual Achievement in Lighting Direction for the episode 'It's A Love Thang' and received multiple additional nominations for the show in subsequent years.