John Thompson II is believed to have been born about 1642, probably in Dorchester or Weymouth, Massachusetts. He was old enough at the time his father moved the family to the Mendon settlement project that he shortly thereafter begins to appear in the early proprietors' records as a member of town planning and development teams.

In 1665, he marries the daughter of one of the founders of Mendon, Thankful Woodland, and becomes a formal landowner in the new town. He remains there for the rest of his life, except for the brief period of exile during King Philip's War, when he appears to have taken temporary refuge in Braintree, outside of Boston.

He and Thankful have ten children together, with his oldest son and namesake, John III, our next grandfather down the Thompson line.