The county was created by the Massachusetts General Court on May 10, 1643, when it was ordered that "the whole plantation within this jurisdiction be divided into four shires."

Middlesex initially contained Charlestown, Cambridge, Watertown, Sudbury, Concord, Woburn, Medford, and Reading.

In 1855, the Massachusetts State Legislature created a minor Registry of Deeds for the Northern District of Middlesex County in Lowell.

[4] Immediately prior to its dissolution, the executive branch consisted of three County Commissioners elected at-large to staggered four-year terms.

The votes of the individual members of the advisory board were weighted based on the overall valuation of property in their respective communities.

[19] Additionally, all county maintenance and security employees were absorbed into the corresponding staffs of the Massachusetts Trial Court.

In Middlesex County (as in the entirety of the Commonwealth of Massachusetts), the governmental functions such as property tax assessment and collection, public education, road repair and maintenance, and elections were all conducted at the municipal city and town level and not by the county government.

In 2012 the 22-story Superior Court Building in Cambridge which was transferred from the abolished Executive County government was sold[23][24] by the Commonwealth of Massachusetts.

[25] Due to its transfer from state control,[26] many local residents had tried to force the private developers to reduce the overall height of the structure.

[27][28] Even following the abolition of the executive branch for county government in Middlesex, communities are still granted a right by the Massachusetts state legislature to form their own regional compacts for sharing of services and costs thereof.

The office of sheriff was created in 1692, making it one of the oldest law enforcement agencies in the United States.

This has been even more apparent in recent years, with George H. W. Bush in 1988 being the last Republican presidential candidate to manage forty percent of the county's votes and Mitt Romney in 2012 being the last Republican presidential candidate to manage even thirty percent of the vote.

Most municipalities in Middlesex County have a town form of government; the remainder are cities, and are so designated on this list.

Villages listed below are census or postal divisions but have no separate corporate or statutory existence from the cities and towns in which they are located.

Founded in 1982 at the end of the United States Bicentennial celebration, the group performs extensively throughout New England.