Upton was originally the home of the Nipmuc, who inhabited most of central Massachusetts. The town was first settled in 1728 and was officially incorporated in 1735.
Upton was home to a number of members of the Taft family, including an American Revolutionary War soldier named Samuel Taft, who was born there. Samuel Taft had 22 children and hosted President George Washington on his inaugural tour of New England in 1789. Three-term mayor of Worcester, historian Judge Henry Chapin was born here on May 13, 1811.
Between 1730 and 1850, Upton had many small shoe shops, called ten–footers. These operations were gradually merged into large assembly-line manufacturing companies. By 1837, Upton produced 21.7% of the boots made in Worcester County.
William Knowlton founded what was to become the world’s largest women's hat factory: Knowlton Hat Factory was built in 1872 and added to the National Historic Register in 1982.
The band Aerosmith played their first gig in 1970 at the then Nipmuc Regional High School, now called Upton-Mendon Regional High School.