Subsequent to its founding as GAME in 1973,[2] with New York City in a deep fiscal crisis, and school art, music, and cultural programs eliminated, a loosely organized, group of artists and educators set up a basement storefront to serve Harlem and the Upper West Side.

With a challenge grant from the National Endowment for the Arts, a city-owned courthouse at 314 West 54th Street was renovated into a small exhibition, studio, and workshop and renamed the Manhattan Laboratory Museum.

CMOM's Executive Director, Andy Ackerman, served as president of the Association of Children’s Museums and hosted the 1999 ACM annual conference.

[8] In January 2018, the Children's Museum of Manhattan announced that it had acquired the former First Church of Christ, Scientist building at 96th Street and Central Park West, and planned to move to the new facility after making renovations.

[11] The original plan for the church was controversial, as residents opposed the addition of a penthouse on the roof and the removal of windows,[12] but FXCollaborative's proposal was ultimately approved in June 2020.