The series was created because Warner Bros. network executives wanted Pinky and the Brain to become more of a sitcom 'like The Simpsons', leading them to have the duo adopted by Elmyra Duff and moved to America's suburbs.

The idea of merging Pinky and the Brain with Elmyra Duff reportedly met with resistance from the original show's producers, who were unhappy with the network's decision.

Producer Peter Hastings, before leaving Warner Bros. for Disney Television Animation, wrote the Pinky and the Brain episode 'You'll Never Eat Food Pellets in This Town Again!', in which the demise of the characters is caused by network decisions to change the show, reflecting the staff's dissatisfaction with the spin-off.

The show's theme song included the pointed lyric 'So Pinky and the Brain share a new domain. It's what the network wants, why bother to complain?', accompanied by an animated shot of Pinky and the Brain being kicked out of the Warner Bros. office.

At the end of the theme song, the Brain delivers a spoken line stating 'I deeply resent this,' further underscoring the characters' (and creators') dissatisfaction with the format change.

Rob Paulsen won the 1999 Annie Award for Outstanding Individual Achievement for Voice Acting for his role as Pinky, beating out co-star Cree Summer who was also nominated for voicing Elmyra.

The show was nominated for the Daytime Emmy Award for Outstanding Children's Animated Program in 1999 (losing to Arthur) but won the award the following year in 2000.

Less than halfway through its run, the series stopped airing as standalone episodes and instead had its episodes split into 10-11 minute segments broadcast within The Cat&Birdy Warneroonie PinkyBrainy Big Cartoonie Show, with episode 10 being the sole exception aired intact.