On April 19, 1775, Middlesex was site of the first armed conflict of the American Revolutionary War.
In 1855, the Massachusetts State Legislature created a minor Registry of Deeds for the Northern District of Middlesex County in Lowell.
In the late 19th century and early 20th century, Boston annexed several of its adjacent cities and towns including Charlestown and Brighton from Middlesex County, resulting in an enlargement and accretion toward Suffolk County.
Beginning prior to dissolution of the executive county government, the county comprised two regions with separate county seats for administrative purposes:
The Middlesex-North District (smaller) with its county seat in Lowell under the Registry of Deeds consisted of the city of Lowell, and its adjacent towns of Billerica, Carlisle, Chelmsford, Dracut, Dunstable, Tewksbury, Tyngsborough, Westford and Wilmington.
The Middlesex-South District (larger) with the county seat in Cambridge consisted of the remaining 44 cities and towns of Middlesex County.
Hillsborough (NH), Essex, Suffolk, Norfolk, and Worcester counties.