The Pennacook were one of the first tribes to encounter European colonists. Soon after contact, like so many other New England Tribes, the Pennacook populations was decimated by infectious diseases. Suffering high mortality, they were in a weakened state and subject to raids by Mohawk of the Iroquois Confederacy from the west, and Micmac tribes from the north, who also took a toll of lives. Chief Passaconaway had a military advantage over the New England colonists, but he decided to make peace with them rather than lose more of his people's lives through warfare.

After becooming caught up in King Philip's War, they lost more members. Although Wonalancet, the chief who succeeded Passaconaway, tried to maintain neutrality in the war, bands in western Massachusetts did not. The Pennacook fled north with their former enemies, or west with other tribes, where the English colonists hunted them down and killed them. Those that survived, joined other scattered tribespeople at Schaghticoke, New York. Those who fled northward eventually merged with other displaced New England tribes and Abenaki. Although no longer a distinct tribe, many bands of Abenaki in New Hampshire, Vermont and Canada, are descended from such Pennacook ancestors.

The Pennacook women cultivated varieties of maize, corn, and squash along fertile river beds, processing them for food and seeds for the next seasons. The men hunted in the wooded, less fertile areas. The name Pennacook roughly translates in Abenaki as "at the bottom of the hill."