The Science and Industry Museum traces its existence back to 1963, when a joint committee was formed to investigate the establishment of a museum of science and industry in Manchester. The committee consisted of representatives from the University of Manchester Institute of Science and Technology (UMIST), the University of Manchester, and Manchester City Council.

In 1965, the Department of the History of Science and Technology at UMIST began to collect historic artefacts to form the basis for the new museum. The Museum originally opened in October 1969 in premises on Grosvenor Street, Manchester.

In 1972, the Museum changed its name to the North Western Museum of Science and Industry, to reflect the regional scope of its collections. The Museum had rapidly outgrown its original premises, but the creation of Greater Manchester County Council (GMC) in 1974 and the closure of Liverpool Road Station by British Rail in 1975 provided the solution to its accommodation problem. GMC became firstly a co-funder of the Museum and then, following the decision to acquire the historic station to house the Museum, the sole funder. This brought a change of emphasis in collecting. Reborn as the Greater Manchester Museum of Science and Industry in 1983, the Museum narrowed its primary geographical focus to Greater Manchester. The site itself, the world’s oldest surviving passenger railway station, is treated as part of the Museum’s collections.

In 1985, the Museum was asked to take over the adjacent Air and Space Museum, which had been set up and run by Manchester City Council. As a result of the abolition of Greater Manchester Council in 1986, the Museum secured ongoing revenue funding from the then Office of Arts and Libraries (later the Department of Culture, Media and Sport and currently the Department for Digital, Culture, Media and Sport). The Museum name changed to the Museum of Science and Industry in Manchester, or MSIM, around this time.

In 2007, the Museum was rebranded as MOSI.

The Museum joined the Science Museum Group in 2012. It was rebranded to become the Museum of Science and Industry in 2015, and subsequently the Science and Industry Museum in 2018.