Hit-Monkey was announced in February 2019 as part of a group of Marvel Television series for Hulu, alongside M.O.D.O.K. and planned shows based on Tigra and Dazzler and Howard the Duck, all intended to lead to a crossover special titled The Offenders.

In January 2020, Marvel decided not to move forward with Howard the Duck, Tigra & Dazzler, and The Offenders crossover, leaving only M.O.D.O.K. and Hit-Monkey to continue as planned.

Oversight of the series moved from Marvel Television to Marvel Studios in December 2019 after Marvel Television was folded into Marvel Studios.

After M.O.D.O.K. was cancelled in May 2022, Variety reported that Hit-Monkey was also not expected to be renewed, but the series was ultimately renewed for a second season in February 2023.

For the second season, production duties shifted to 20th Television Animation since Marvel Television no longer existed, and it was initially reported the show would drop 'Marvel's' from its title, though the second season was ultimately still formally called Marvel's Hit-Monkey.

M.O.D.O.K. co-creator Jordan Blum noted that Hit-Monkey has a distinctly different animation style compared to M.O.D.O.K., despite both being adult animated Marvel series developed around the same time.

Casting for the lead roles, including Jason Sudeikis as Bryce and Fred Tatasciore as Monkey, alongside George Takei, Olivia Munn, Ally Maki, and Nobi Nakanishi, was revealed in September 2021 shortly before the show's premiere.

For season two, Leslie Jones and Cristin Milioti joined the cast as new characters Eunice Jones and Iris McHenry, with the latter having first appeared as a child character in the first season.