Wilmington was first settled in 1665 and was officially incorporated in 1730, from parts of Woburn, Reading, and Billerica. The first settler is believed to have been Will Butter, Richard Harnden or Abraham Jaquith. Butter was brought to Woburn as an indentured captive. Once he attained his freedom, he fled to the opposite side of a large swamp, in what is now Wilmington. Harnden settled in Reading, in an area that is now part of Wilmington. Jaquith settled in an area of Billerica that became part of Wilmington in 1737.

Minutemen from Wilmington responded to the alarm on April 19, 1775 and fought at Merriam's Corner in Concord.

The Middlesex Canal passed through Wilmington. Chartered in 1792, opened in 1803, it provided freight and passenger transport between the Merrimack River and Boston. One important cargo on the canal was hops. From the middle of the 18th century until the early 19th century, Massachusetts was the acknowledged leader in hop production in North America. Middlesex County in particular was famous for its hop yards, and Wilmington was the first place where the culture grew to a fever pitch.

When Lowell was built in the 1820s, the canal became a primary means of transporting cotton to and from the mills. It was abandoned in 1852 after the construction of the Boston and Lowell Railroad.

The Boston and Lowell Railroad was built in 1835. The line is now the oldest operating rail line in the U.S. Wilmington is also served by the Haverhill Division (the old B&M Portland Division). A spur track known as the Wildcat connects the Haverhill and Lowell divisions, following the path of the old Wilmington & Andover Railroad, the corporate ancestor of the Boston & Maine.

Wilmington is where the Baldwin apple was discovered.

Wilmington is also home to the Col. Joshua Harnden Tavern, which probably served as a stop on the underground railroad and now houses the Wilmington Town Museum.

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