Yorkshire County was established in 1652 to include the area of the proprietary province of Lygonia when the Massachusetts Bay Colony first asserted territorial claims over the settlements in the southern parts of the Province of Maine, extending from the Piscataqua River to just east of the mouth of the Presumpscot River in Casco Bay.
The county eventually grew to encompass effectively all of present-day State of Maine, although the interior was claimed by various Abenaki peoples, and the territory east of Penobscot Bay was claimed (and partly occupied) as part of French Acadia.
However, the land east of the Kennebec River was claimed and sometimes administered as Cornwall County, Province of New York from September 5, 1665.
By 1760, most of the Abenaki had either been wiped out or retreated northward toward the Saint Lawrence River, and New France had been conquered in the French and Indian War.
When the 1780 Constitution of Massachusetts was adopted, the state created the District of Maine to manage its eastern territories.