Moesha was originally ordered as a pilot for CBS during the 1995–1996 television season but was declined by the network before being picked up by the newly launched UPN, which aired it as a mid-season replacement starting January 23, 1996.

The series went on to become the biggest success for the nascent UPN network and remained one of the greatest hits over the course of the network's entire run.

The show was notable for featuring the first Black-cast sitcom episode devoted to teenagers and non-heterosexuality, titled 'Labels,' which aired on October 1, 1996.

Sheryl Lee Ralph, who played stepmother Dee, left her role as a main cast member after season 5 because she did not appreciate the storyline revealing that Frank was the biological father of Dorian.

Countess Vaughn left Moesha after its fourth season to star in her own spin-off series The Parkers alongside Mo'Nique, while Yvette Wilson also departed to join that same spin-off as Andell Wilkerson.

Although not a direct spin-off, the series Girlfriends, created by Moesha writer Mara Brock Akil, exists in the same fictional universe: its character Maya Wilkes lives in the same Leimert Park neighborhood and is connected to Dorian's birth mother Barbara Lee, while Niecy from Moesha made a guest appearance in a season 1 episode of Girlfriends.

On Moesha, star Brandy played herself as a celebrity doppelganger to her character, which became ironic when Brandy later joined the spin-off universe series The Game in its fifth season as a different character, Chardonnay Pitts.

The series ended in 2001 on an unresolved cliffhanger involving a kidnapping and an unidentified positive pregnancy test, and Entertainment Weekly reported rumors that these plots were meant to be resolved on The Parkers, though they never were.