The Main Street Gallery opened its doors in October 2008, under the auspices of Cambridge Main Street, a 501c3 non-profit organization active in promoting and preserving historic Cambridge. The gallery is housed in a restored space that was once the storage area of a former McCrory's five-and-dime store, which had been vacant for several years. Renovation was made possible by a $100,000 grant and the participation of NOVO Development.
The restoration retained the original tin ceilings and many other historical architectural features, but gave the gallery the face of an elegant avant garde venue.
The gallery first opened its doors during an ambitious found art show featuring art made from reused items and cast-offs. The exhibit, "Another Man's Treasure: The Art of the Found Object" drew many visitors and established the gallery as a force in the Cambridge art world, which later extended to Dorchester County and the Eastern Shore.
As of July 1, 2011, the gallery entered a new and exciting phase of its history as it began the transition to an artist-run facility. After a year and a half at the 413 Muir Street address, the Main Street Gallery relocated to 447 Race Street in December 2012. As of August 2014 the Gallery is now located closer to the downtown area at 518 Poplar Street.