The roots of the massacre reach back to competition, not ideology. The Pequots were the dominant tribe in southeastern Connecticut, controlling a territory that English settlers increasingly coveted. The Pequots had long been rivals of the neighboring Mohegan and Narragansett tribes, and as European colonists established trade networks exchanging manufactured goods for wampum and furs, these old enmities acquired new and dangerous dimensions. The Pequots allied with the Dutch; the Mohegans and Narragansetts allied with the English. When a trader named John Oldham was murdered and his ship looted by Pequots, it provided a pretext for military action. But the deeper catalyst may have been environmental. The Great Colonial Hurricane of 1635 devastated corn and other crop harvests across New England, making food supplies desperately scarce. The resulting competition for dwindling winter provisions pushed tensions between colonists and Pequots past the breaking point.

Captain John Mason raised his militia from the Connecticut towns. Seventy Mohegans under sachems Uncas and Wequash joined him, and Captain John Underhill brought twenty more men from Fort Saybrook. Mason then recruited over 200 Narragansett and Niantic warriors. On the evening of May 26, this combined force approached the fortified Pequot village, a settlement surrounded by a wooden palisade with only two narrow exits. The colonists attempted a direct assault first, pushing through one of the entrances. The Pequots fought back fiercely, and the attackers withdrew. Mason then made the decision that would define the encounter: he ordered the village burned. His men set fire to the wigwams inside the palisade while blocking both exits. As flames consumed the village, Pequots who attempted to climb over the palisade walls were shot. Those who made it over were killed by the Narragansett warriors stationed in a ring outside. The colonists reported that only five Pequots escaped the encirclement. Seven were taken prisoner.

The massacre broke the Pequot nation. Estimates of Pequot dead range from 400 to 700, nearly all of them noncombatants, since the Pequot warriors under sachem Sassacus had departed days earlier on a raiding party aimed at Hartford. The colonists suffered between 22 and 26 casualties, with only two confirmed dead. Approximately 40 Narragansett warriors were wounded, many of them shot by colonists who mistook them for Pequots in the chaos. Sassacus and his returning warriors discovered the devastation and pursued Mason's retreating forces, but the colonists avoided a counterattack. Sassacus and his remaining followers were later cornered in a swamp near a Mattabesset village in what became known as the Fairfield Swamp Fight, where nearly 180 warriors were killed, wounded, or captured. Sassacus escaped with roughly 80 men but was killed by the Mohawks, who sent his scalp to the English colonists as a gesture of alliance. The Treaty of Hartford in 1638 imposed conditions designed to erase the Pequots entirely: they were prohibited from returning to their lands, speaking their language, or even referring to themselves as Pequots.

For centuries, the Mystic massacre was framed as a battle rather than what modern scholars increasingly recognize it as: an act of genocide. During the 1990s, as the Pequot nation reemerged as a federally recognized tribe, The New England Quarterly published arguments examining whether the massacre constituted genocide. Rebecca Joyce Frey listed it as such in her 2009 book Genocide and International Justice. Steven M. Wise of Harvard Law School called it "the Puritans' genocidal Indian War." The statue of Captain Mason, originally erected at the massacre site in 1889, was moved to Windsor in 1996. In 2020, following national debates over Confederate monuments, Windsor's town council voted 5-4 to remove it. The History Channel featured the event in its series 10 Days That Unexpectedly Changed America, placing the Mystic massacre alongside Antietam and other watershed moments. The Pequots' own survival is perhaps the most powerful rebuttal to the Treaty of Hartford's attempt at cultural annihilation: the Mashantucket Pequot Tribal Nation operates one of the largest museum and research centers dedicated to Native American history in the northeastern United States.

The site of the massacre lies near the Mystic River in southeastern Connecticut, a landscape of tidal marshes, stone walls, and quiet neighborhoods that gives little outward indication of what occurred here nearly four centuries ago. The low hill where the palisade stood has been absorbed into the modern town of Mystic, better known today for its seaport museum and tourist trade than for the violence that marks its earliest colonial history. From above, the Mystic River curves gently through salt marshes toward Long Island Sound, and the terrain looks much as it would have in 1637, minus the forest that once covered these hills. The Pequot people survived what was meant to destroy them completely. Their story, and the story of what happened on this hill in the predawn hours of a May morning, endures as a reminder that the founding of New England was not a peaceful enterprise, and that the land beneath the flight path carries memories far older and more complicated than its postcard appearance suggests.