After twelve years of peace following the Indian Wars of 1622-1632, another Anglo–Powhatan War began on March 18, 1644, as a last effort by the remnants of the Powhatan Confederacy, still under Opechancanough, to dislodge the English settlers of the Virginia Colony. Around 500 colonists were killed, but that number represented a relatively low percent of the overall population, as opposed to the earlier massacre (the 1622 attack had wiped out a third; that of 1644 barely a tenth). However, Opechancanough, still preferring to use Powhatan tactics, did not make any major follow-up to this attack.
This was followed by a last effort by the settlers to decimate the Powhatan. In July, they marched against the Pamunkey, Chickahominy, and Powhatan proper; and south of the James, against the Appomattoc, Weyanoke, Warraskoyak, and Nansemond, as well as two Carolina tribes, the Chowanoke and Secotan.
In February 1645, the colony ordered the construction of three frontier forts: Fort Charles at the falls of the James, Fort James on the Chickahominy, and Fort Royal at the falls of the York. In August, Governor William Berkeley stormed Opechancanough's stronghold and captured him. All captured males in the village over age 11 were deported to Tangier Island. Opechancanough, around 92 years old, was taken to Jamestown where he was shot in the back by a guard. Opechancanough's death resulted in the disintegration of the Powhatan Confederacy into its component tribes, whom the colonists continued to attack. In March 1646, the colony decided to build a fourth frontier fort, Fort Henry, at the falls of the Appomattox, where the modern city of Petersburg is located.