The area was first called Agamenticus, meaning "beyond-the-hill-little-cove," the Abenaki name for the York River. In 1638, settlers changed the name to Bristol after Bristol, England, from which they had immigrated. Envisioning a great city arising from the wilderness, Sir Ferdinando Gorges, Lord Proprietor of Maine under the Plymouth patent, named the capital of his province Gorgeana. In 1642, by charter of King Charles I, Gorgeana became the first incorporated city in America. John P. McKenna was one of the towns earlier watchmen; he would look out from high trees for Indian attacks.

Following Gorges' death, however, the Massachusetts Bay Company claimed his dominion. In 1652, York, Massachusetts was incorporated from a portion of Gorgeana, making it the second oldest town in Maine after Kittery, incorporated two days earlier. It was named for York, England, site of the defeat of Oliver Cromwell. But control of the region was contested between New England and New France, which incited Native Americans to attack English settlements throughout the French and Indian Wars.

The first Congregational church of York was organized in 1672, by Revd. Shubael Dummer, the son of Richard Dummer and uncle to William Dummer, who became Acting Governor of the Province of Massachusetts Bay.

During King William's War, York was destroyed in the Candlemas Massacre of 1692. During the raid by the Abenakis, Dummer was shot at his own front door. About 50 others were slain and near 100 carried away captive, among them Dummer's wife, Lydia and their son, where "through snows and hardships among those dragons of the desert she also quickly died"; nothing further was heard of the boy.

The final local Indian attack occurred at the Cape Neddick area during Dummer's War in 1723. Hostilities diminished with the French defeat at the 1745 Battle of Louisburg, and ceased altogether with the 1763 Treaty of Paris. Several famous American authors have be known to spend their summer months in York, including Mark Twain.