The French and Indian War was the North American phase of a worldwide conflict between Britain and France. In Europe the conflict was called the Seven Years' War (1756—1763), but its Ohio Valley phase cannot be dated with such precision. Although commonly dated to 1754, the war may be said to have begun as early as 1752, when the French destruction of a pro-British Miami village in western Ohio helped to bring the Shawnees, Delawares, and other Ohio Indians into the French orbit. In 1753, the governor of Virginia dispatched the young George Washington to the upper Ohio to warn the French away from the valley. In 1754, Washington returned with troops to seize the region's most strategic point, the Forks of the Ohio at modern Pittsburgh, defeated a French detachment, and was defeated in turn when the French and their Indian allies forced his surrender at Fort Necessity on July 3. Shortly thereafter an Indian attack wiped out the first attempted white settlement in Tygart Valley near the Monongahela headwaters.

The Indians confronted the oncoming conflict with fear and resentment. Now dependent upon European manufactured goods, they appreciated the lower prices and better quality they got from British traders but recognized that the French posed less of a threat to their hunting grounds than the land-hungry Virginians and Pennsylvanians. The French thrust toward the Ohio, coupled with Virginia's land hunger and the official pacifism of Quaker Pennsylvania, left the Ohio Indians little choice but to join with the French.

British authorities dispatched Maj. Gen. Sir Edward Braddock and 1,400 regular troops to the Ohio frontier in 1755. Braddock accepted Virginia militia and supplies from Pennsylvania but arrogantly ignored colonial advice about how to fight in Indian country. He led his army into one of the worst defeats in frontier history when he blundered into a French and Indian ambush at the Battle of the Monongahela, near present Pittsburgh, on July 9. Braddock was killed, and other participants, such as Washington, Andrew Lewis, and a young teamster named Daniel Boone, barely managed to make their way back to the settlements. A general assault followed on the Virginia frontier by Shawnee, Delaware, and Mingo war parties. Settlers newly planted in the Greenbrier and upper New River valleys were killed, captured, or frightened back across the mountains, while the older settlements in the South Branch and Potomac valleys came under heavy assault. Here a minority of residents held their ground, backed by a chain of small forts that Washington organized in 1756.

Virginia's government responded to Braddock's defeat by raising an army of several hundred frontiersmen commanded by Andrew Lewis and joined by around 100 Cherokee warriors. Lewis's orders were to march toward the Ohio via "Sandy Creek" (the Big Sandy River) and destroy the Shawnee villages in southern Ohio. Disaster again followed. Ill-disciplined, poorly supplied, and unlucky in the weather and scarcity of game they encountered, this Sandy Creek Expedition struggled forward for nearly a month in February—March 1756 before turning back in a state of near-starvation and mutiny.

The Western Virginia frontier remained open to assault until British regulars under Gen. John Forbes drove the French away from the Forks of the Ohio, present Pittsburgh, and established Fort Pitt there in 1758. This brought the Ohio Indians back under British influence, though occasional Indian raids into Virginia continued in 1759 and 1760. When defeats in Europe, India, and the Caribbean led the French to accept a general settlement in 1763, they agreed to give up all their North American territory. The astonished Indians, who did not consider themselves to have been conquered in battles fought far away in Canada and overseas, then confronted victorious British officials who to them seemed to have combined the imperious attitude of the French with the greed of the frontiersmen. The result was further native resistance, in an episode known to history as "Pontiac's Rebellion," when assaults again fell on the Greenbrier, Monongahela, and Potomac frontiers. Finally, in 1764, an uneasy peace settled over the Ohio Valley, though the basic issue of who would control the region remained unsettled.