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Prior to European colonization, the region around Framingham was inhabited by the indigenous Nipmuc. They lived in settlements established alongside the Washakamaug (“eel fishing place”) or what is today called Farm Pond. The Nipmuc people used game management techniques through the hunting of deer and beaver, fishing in ponds and streams, as well as established growing areas for the Three Sisters (squash, corn, beans) in the nearby hills. The ancient Native trail later known as the Old Connecticut Path also ran through this area. During the initial period of colonization of the region by Puritan settlers, the Nipmuc suffered a rapid decline in population due to the introduction of foreign infectious diseases to which they had no immunity and violence related to settler colonialism. Many of the Nipmuc people were forced into praying towns including nearby Natick.

The first European settler in the area was John Stone who established a farm on the west bank of the Sudbury River in 1647. In 1660, Thomas Danforth, an official of the Bay Colony received a grant of land at “Danforth’s Farms” and began to accumulate over 15,000 acres (100 km²).

Between 1675 and 1676, King Philip’s War created great tensions between English settlers and the Nipmuc people in the area. During this time, Nipmuc leader Tantamous, who lived on Nobscot Hill and who resisted Christianization by the English, was arrested with his family members and other Nipmuc men by the colonial government in 1676 for what the colony deemed treason and they were incarcerated on Deer Island. He would escape, be recaptured, and later hung on Boston Common. In January 1676, a group of Nipmuc men went to the Eames family homestead to demand that they return a stolen corn harvest. Although the historical record is unclear as to the exact details, this would result in an outbreak of violence between the Nipmuc men and the Eames family, where Mary Eames and five children were killed.