The Indian massacre of 1622, popularly known as the Jamestown massacre, took place in the English Colony of Virginia, in what is now the United States, on 22 March 1622. John Smith, though he had not been in Virginia since 1609 and was not an eyewitness, related in his History of Virginia that warriors of the Powhatan "came unarmed into our houses with deer, turkeys, fish, fruits, and other provisions to sell us". The Powhatan then grabbed any tools or weapons available and killed all the English settlers they found, including men, women, children of all ages. Chief Opechancanough led the Powhatan Confederacy in a coordinated series of surprise attacks, and they killed a total of 347 people, a quarter of the population of the Virginia colony.

Jamestown, founded in 1607, was the site of the first successful English settlement in North America, and was the capital of the Colony of Virginia. Its tobacco economy, which quickly degraded the land and required new land, led to constant expansion and seizure of Powhatan lands, which ultimately provoked the massacre.