Unlike other Monsters, Inc. franchise productions, this series was not produced by Pixar itself but by Disney Television Animation, making it the studio's second series based on a Pixar film after Buzz Lightyear of Star Command.

Bob Iger announced the series during Disney's November 2017 earnings call as part of the lineup for the upcoming Disney+ streaming service.

Showrunner Bobs Gannaway said it took the producers almost a year to conceive the series' premise, and he compared Tylor's struggles adapting to a new job to the real-world upheaval caused by the COVID-19 pandemic.

Fear Co., the rival company featured in season 2, was actually planned for the original Monsters, Inc. film before being cut, and was later revived for the series.

To research what it's like to work in a factory setting, the production team visited two real power plants and interviewed workers about their daily routines, with Gannaway stating he wanted to 'tether everything to truth.'

Animation work began shortly before Disney Television Animation temporarily closed due to the COVID-19 pandemic, forcing the crew to continue storyboard and layout work remotely for the second and third episodes.

Gannaway initially chose not to include the characters Smitty and Needleman out of respect for their late voice actor Dan Gerson, who died in 2016, but eventually included them and paid tribute to him with a 'Gerson Industries' logo on the trash cans they push.

To keep Steve Buscemi's return as Randall Boggs a secret in season 2, the production script referred to the character as 'Edward', named after executive producer Edward Mejia.

Gannaway confirmed that Boo, the human child from the original film, would not appear in the series, as he and director Pete Docter deliberately wanted to keep her relationship with Sulley and Mike ambiguous.

Composer Dominic Lewis based the score largely on Randy Newman's jazzy music from the original film and personally performed the show's a cappella theme song, an arrangement of Newman's original opening credits music.