The first native settlers in southern West Virginia were the Mound Builders, also known as the Adena people. Remnants of the Mound Builder=s civilization have been found throughout West Virginia, with a high concentration of artifacts located at Moundsville, West Virginia, in Marshall County.

According to missionary reports, several thousand Hurons occupied present-day West Virginia during the late 1500s and early 1600s. The Iroquois Confederacy (consisting of the Mohawk, Onondaga, Cayuga, Oneida and Seneca tribes, and joined later by the Tuscaroras tribe) drove the Hurons out of the state during the 1600s. The Iroquois Confederacy was headquartered in New York and was not interested in occupying present-day West Virginia. Instead, they used it as a hunting ground during the spring and summer months.

During the early 1700s, southern West Virginia, including present-day Wyoming County, was used as a hunting ground by the Mingo, who lived in both the Tygart Valley and along the Ohio River in West Virginia=s northern panhandle region, the Delaware, who lived in present-day eastern Pennsylvania, New Jersey, and Delaware, but had several autonomous settlements as far south as present-day Braxton County, the Shawnee, and by other members of the Iroquois Confederacy, especially the Seneca, one of the largest and most powerful members of the Iroquois Confederacy.

The Mingo were not actually an Indian tribe, but a multi-cultural group of Indians that established several communities within present-day West Virginia. They lacked a central government and, like all other Indians within the region at that time, were subject to the control of the Iroquois Confederacy. The Mingo originally lived closer to the Atlantic Coast, but European settlement pushed them into western Virginia and eastern Ohio.

The Seneca, headquartered in western New York, was the closest member of the Iroquois Confederacy to West Virginia and took great interest in the state. In 1744, the Seneca boasted to Virginia officials that they had conquered the several nations living on the back of the great mountains of Virginia. Among the conquered nations were the last of the Canawese or Conoy people who became incorporated into some of the Iroquois communities in New York. The Conoy continue to be remembered today through the naming of two of West Virginia's largest rivers after them, the Little Kanawha and the Great Kanawha.

The Seneca and other members of the Iroquois Confederacy often traveled through the state to protect its claim to southern West Virginia from the Cherokee. The Cherokee were headquartered in western North Carolina and eastern Tennessee and rivaled the Iroquois nation in both size and influence. The Cherokee claimed present-day southern West Virginia as their own, setting the stage for conflict with the Iroquois Confederacy.

In 1744, Virginia officials purchased the Iroquois title of ownership to West Virginia in the Treaty of Lancaster. The treaty reduced the Iroquois Confederacy's presence in the state.

During the mid-1700s, the English had made it clear to the various Indian tribes that they intended to settle the frontier. The French, on the other hand, were more interested in trade. This influenced the Mingo to side with the French during the French and Indian War (1755-1763). Although the Iroquois Confederacy officially remained neutral, many in the Iroquois Confederacy also allied with the French. Unfortunately for them, the French lost the war and ceded the all of its North American possessions to the British. Following the war, the Mingo retreated to their homes along the banks of the Ohio River and were rarely seen in southern West Virginia.

Although the war was officially over, many Indians, especially the Shawnee who resided in Ohio, continued to see the British as a threat to their sovereignty and continued to fight them. In the summer of 1763, Pontiac, an Ottawa chief, led raids on key British forts. Shawnee chief Keigh-tugh-qua, or Cornstalk, led similar attacks on western Virginia settlements in present-day Greenbrier County. By the end of July, Indians had captured all British forts west of the Alleghenies except Detroit, Fort Pitt, and Fort Niagara. Then, on August 6, 1763, British forces under the command of Colonel Henry Bouquet retaliated and destroyed Delaware and Shawnee forces at Bushy Run in western Pennsylvania, ending the hostilities. Fearing more tension between Native Americans and settlers, England's King George III issued the Proclamation of 1763, prohibiting settlement west of the Allegheny Mountains. However, many land speculators, including George Washington, violated the proclamation by claiming vast acreage in western Virginia. In 1768, the Iroquois Confederacy (often called the Six Nations) and the Cherokee signed the Treaty of Hard Labour and the Treaty of Fort Stanwix, relinquishing their claims on the territory between the Ohio River and the Alleghenies to the British. With the frontier now open, settlers, once again, began to enter into present-day West Virginia.

In 1772, a series of incidents between settlers and Indians in West Virginia ended what had been nearly eight years of peace. During the spring of that year, several Indians were murdered on the South Branch of the Potomac River by Nicholas Harpold and his companions. About the same time, Bald Eagle, an Indian chief of some notoriety, was murdered while on a hunting trip on the Monongahela River. In the meantime, Captain Bull, a Delaware Indian Chief and five other Indian families were living in Braxton County in an area known as Bulltown, near the falls of the Little Kanawha River, about fourteen miles from present day Sutton. Captain Bull was regarded by most of the settlers in the region as friendly. But some settlers suspected him of providing information to and harboring unfriendly Indians. While away from home in June 1772, the family of a German immigrant named Peter Stroud was murdered, presumably by Indians. The trail left by the murderers led in the general direction of Bulltown. Peter's brother, Adam Stroud, had a cabin nearby and seeing smoke rising into the sky, raced to his brother's cabin. He gathered up what was left of the bodies and buried them. He then headed for Hacker's Creek where he met with several other settlers who agreed to join him in an attack on Bulltown. They killed all of the Indians in the village, including Captain Bull, and threw their bodies into a nearby river. News of Captain Bull's murder quickly spread across the western frontier. Following what the Indians referred to as the Bulltown massacre, Shawnee Chief Cornstalk, who had led numerous raids against West Virginia settlers in the past, began to organize the Indians in a concerted effort to drive the whites from their territory.

In 1773, land speculator Michael Cresap led a group of volunteers from Fort Fincastle (later renamed Fort Henry) at present-day Wheeling, murdering several Shawnee at Captain Creek. Among other atrocities, on April 30, 1774, colonists murdered the family of Mingo chieftain Tah-gah-jute, who had been baptized under the English name of Logan. Although Logan had previously lived peacefully with whites, he killed at least thirteen settlers that summer in revenge.

Virginia Governor John Murray, Earl of Dunmore, worried about the escalating violence in western Virginia, decided to end the conflict by force. He formed two armies, one marching from the North, consisting of 1,700 men led by himself and the other marching from the South, comprised of 800 troops led by western Virginia resident and land speculator Captain Andrew Lewis. Shawnee chieftain Keigh-tugh-qua, or Cornstalk, along with approximately 1,200 Shawnee, Delaware, Mingo, Wyandotte and Cayuga warriors, decided to attack the southern regiment before they had a chance to unite with Lord Dunmore's forces. On October 10, 1774, the Indians attacked Lewis' forces at the confluence of the Kanawha and Ohio Rivers, at present-day Point Pleasant, in Mason County. During the battle, both sides suffered significant losses.

Although nearly half of Lewis' commissioned officers were killed during the battle, including his brother, Colonel Charles Lewis, and seventy-five of his non-commissioned officers, the Indians were finally forced to retreat back to their settlements in Ohio's Scioto Valley, with Lewis' men in pursuit. In the meanwhile, Lord Dunmore arrived and joined forces with Lewis. Seeing that they were now outnumbered, Cornstalk sued for peace.

Although western Virginia's settlers continued to experience isolated Indian attacks for several years, Cornstalk's defeat at Point Pleasant was the beginning of the end of the Indian presence in western Virginia. The Indians agreed to give up all of their white prisoners, restore all captured horses and other property, and not to hunt south of the Ohio River. Also, they were to allow boats on the Ohio River and promised not to harass them. This opened up present-day West Virginia and Kentucky for settlement. Cornstalk was later killed at Fort Randolph near Point Pleasant in 1777 in retaliation for the death of a militiaman who was killed by an Indian.

During the American Revolution (1776-1783), the Mingo and Shawnee, headquartered at Chillicothe, Ohio, allied themselves with the British. In 1777, a party of 350 Wyandots, Shawnees, and Mingos, armed by the British, attacked Fort Henry, near present-day Wheeling. Nearly half of the Americans manning the fort were killed in the three-day assault. The Indians then left the Fort celebrating their victory. For the remainder of the war, smaller raiding parties of Mingo, Shawnee, and other Indian tribes terrorized settlers throughout West Virginia. As a result, European settlement in the state came to a virtual standstill until the war's conclusion. Following the war, the Mingo and Shawnee, once again allied with the losing side, returned to their homes. However, as the number of settlers in the region began to grow, and with their numbers depleted by the war, both the Mingo and the Shawnee moved further inland.