The building was originally built as part of the Boston Manufacturing Company, Francis Cabot Lowell's seminal, fully integrated textile mill.

The museum, which was incorporated in 1980 and opened to the public in 1988, takes up only a small portion of the previous mill building complex.

[1] As part of the site's renovation, a group of cultural, civic, and business leaders led by Michael Folsom, an MIT professor, created the Charles River Museum of Industry & Innovation in what had been the mill's massive steam-powered engine and boiler rooms.

The museum accomplishes this through its collections and programs, by exploring the historical impact of industry on American culture, by examining the dynamic process of innovation, by promoting its location in Waltham as a foundation of the American industrial revolution, by connecting the expertise of older generations with the inquisitiveness of young people, and by providing audiences of all ages with an engaging museum experience.

[3] The museum includes two revolving exhibit spaces that change out anywhere from 3–6 months, covering anything from science and math to cultural investigation.