Abenaki Indians, whose main village was upriver at Pequawket (now Fryeburg), once hunted and fished in the area. The first European to settle at Biddeford was physician Richard Vines in the winter of 1616-1617 at Winter Harbor, as he called Biddeford Pool. This 1616 landing by a European predates the Mayflower landing in Plymouth, Massachusetts, (located 100 miles to the south) by approximately four years, a fact that is overlooked in much of New England lore. The Plymouth Company granted the land south of the River Swanckadocke to Dr. Vines and John Oldham. In 1653, the town included both sides of the river, and was incorporated by the Massachusetts General Court as Saco. In 1659, Major William Phillips of Boston became a proprietor, and constructed a garrison and mill at the falls. During King Philip’s War in 1675, the town was attacked by Indians. Settlers withdrew to Winter Harbor for safety, and their homes and mills upriver at the falls were burned. In 1693, a stone fort was built a short distance below the falls, but it was captured by the Indians in 1703, when 11 colonists were killed and 24 taken captive to Canada. In 1688, Fort Mary was built near the entrance to Biddeford Pool. The town was reorganized in 1718 as Biddeford, after Bideford, a town in Devon, England, from which some settlers had emigrated. After the Fall of Quebec in 1759, hostilities with the natives ceased.
In 1762, the land northeast of the river was set off as Pepperellborough, which in 1805 was renamed Saco. The first bridge to Saco was built in 1767. The river divides into two falls that drop 40 feet (12 m), providing water power for mills. Factories were established to make boots and shoes. The developing mill town also had granite quarries and brickyards, in addition to lumber and grain mills.