The Museum opened on October 3, 1981, as a small regional museum devoted to presenting the works of major Northwest artists in continual exhibition and serving as a source of education on Northwest art. The vision of photographer Art Hupy, the Museum lived for its first 14 years on the second floor of the historical Gaches Mansion in La Conner. As early as 1982 the Museum board began to look for a space more suitable for housing works of art when they contemplated the purchase and renovation of the La Conner Town Hall. Plans for relocation and expansion simmered over the next decade while support for the regional museum grew. During this time the Museum mounted exhibitions designed to illuminate both the artist and their art. Among the many artists shown were Mark Tobey, Joey Kirkpatrick and Flora Mace, Clayton James, Philip McCracken, Mary Randlett, William Ivey, George Tsutakawa, Paul Havas.

In 1991 the Museum board and a legion of volunteers began a major fundraising drive to acquire a new home. About that time, a commercial building in downtown La Conner, featuring 12,000 square feet intended for retail and office space came on the market. After two years of negotiation the deal closed and renovations began. Given a fresh face, inside and out, by the Henry Klein Partnership, Architects, the new building had an elegance befitting a museum destined to attract national attention, and the new Museum of Northwest Art opened its doors to the public in October 1995, 14 years to the day after the original vision got its start.

Paralleling some of the specialized regional museums in Europe, MoNA has stressed high quality standards from the beginning. With no permanent collection initially, the Museum now has a small but fine representative collection of paintings, sculpture, glass and works on paper, numbering approximately 2500 as of early 2009. The mission of the Museum has expanded from its original purpose to showcase just a few major Northwest artists and now offers exhibition opportunities for the many fine artists of the Pacific Northwest, including promising new talent. The building also allows for an increase in educational activities – workshops, tours, lectures and work with school groups.