The national recession from 1989 through 1992 hit New England hard. Maine, like its regional neighbors, sustained job loss, out-migration of talent and government budget deficits. Working through the regional Chamber of Commerce, business, government and educational leadership in Greater Portland posed the question: What kind of help do Maine businesses need to mitigate economic cycles and compete in the global marketplace?

The community hired a nationally prominent economic development consultant who worked with dozens of businesses, agencies and institutions to generate the concept of a regional Enterprise Development Corporation specializing in assistance to entrepreneurs. To put the idea into practice, the community raised several hundred thousand dollars to support a business incubation program for start-up companies focused on environmental technology. In 1996, Southern Maine Technical College (now community college) recruited the fledgling organization to its South Portland campus.

Founded as the Maine Center for Enterprise Development, the 501(c)3 entity operated as the Center for Environmental Enterprise (CEE). In 1997, the center welcomed its first tenant, Terralink Software Systems. In 1999, the Department of Commerce awarded CEE a $200,000 grant, one of only 18 awarded in the nation for innovative technology development programs.

In 2000, the Maine Legislature created a network of seven technology incubators statewide, modeled upon CEE. CEE received $750,000 in state and federal funds to renovate and update its headquarters. In 2003, CEE successfully completed a jobs creation initiative for low and moderate income workers in partnership with the City of South Portland. The South Portland City Council also provided operations support for CEE, providing $75,000 in aid over a three-year period as part of a municipal economic development strategy. Also in 2003, the Maine Legislature honored CEE as the most successful example of business incubation in Maine.

In 2004, MCED moved from the Southern Maine Community College to the University of Southern Maine, where it occupied part of a floor at the new Research Building. In 2009, MCED started a transition away from a traditional incubator to a virtual incubator with the introduction of the Top Gun Program. Top Gun has been offered annually since 2009. With assistance from Blackstone Accelerates Growth and the Maine Technology Institute, the program expanded to 3 locations across the state in Portland, Bangor and Rockland.

With the help of a cluster initiative grant in 2012, MCED (now the Maine Center for Entrepreneurial Development), has worked in close partnership with the University of Maine through the Foster Center for Student Entrepreneurship, the Target Technology Center, and the Maine Aquaculture Innovation Center, the sole remaining technology incubators in the state. This partnership targets and supports innovative, scalable entrepreneurship throughout the state's business sectors.

In 2011, MCED moved away from the University of Southern Maine to commercial space in Portland's Old Port, and in 2012, moved to its current location at 30 Danforth Street.