Milford was first settled in 1662 as a part of Mendon. The King Philip's War destroyed the town in 1676, but settlers returned in 1680. The Mill River flows through Milford and had several conspicuous fords that were familiar to the Native Americans, and used by the early white settlers. These "Mill (river) fords" gave Milford its name. Milford was incorporated April 11th, 1780 and the first Town Hall built in 1819; a brick structure later named the Town House School. The Milford Town Hall was built in 1854 by architect Thomas Silloway.

Milford is renowned for its pink Milford granite, discovered in 1870. Milford quarries fueled the local economy until about 1940.[4] The granite has been used for local buildings such as Memorial Hall, the Bancroft Memorial Library in Hopedale, Worcester City Hall, and the Boston Public Library. Other notable buildings include the original Pennsylvania Station in New York City, the main post office in New York City, and most recently the Singapore Changi Airport in 2002.The Battle Monument at West Point is also made of Milford granite, and is reputed to be the largest column of polished granite in the Western Hemisphere.

The Milford Hospital was donated in 1903 by Governor Eben Sumner Draper. Today, the health care facility exists as the Milford Regional Medical Center. In January 2008, the Center opened a cancer treatment facility with the Dana–Farber Cancer Institute. The Center is affiliated with UMass Medical Center as a teaching hospital.[7] In 2015 the hospital completed a $54 million expansion project that created a new emergency department and updated the intensive care unit, as well as patient rooms.

Milford has been growing at a fast rate since the introduction of Interstate 495, which opened in the area with dual exits at Route 85 and Route 109 in 1969. Since then many major retailers have opened in town. Milford was fictitiously featured in a 2008 episode of the Fox television series Fringe.

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