The Shawnees were the southernmost of the Algonquian-speaking peoples of the eastern woodlands; hence their name, which derives from "southerner" in these languages. Originally centered in the mid-Ohio Valley, they descended, according to some archeologists, from the pre-historic Fort Ancient culture whose remains have been found in the Kanawha Valley, among other places. But they left this homeland during the 17th century, presumably in response to Iroquois attacks during the Beaver Wars, and were recorded by Europeans in such widely separated locations as Kentucky, Alabama, South Carolina, and Pennsylvania. A Shawnee companion of the French explorer, Robert Cavelier de la Salle, even traveled to Paris. The Shawnees entered frontier annals on a regular basis after Quaker missionaries found some of them living on Pequa Creek near present Lancaster, Pennsylvania, in 1692.

It is possible that the 17th century record represents the separate wanderings of the Shawnee's principal divisions—Chalakaatha, Mequashake, Pekowi, Hathawikila, and Kishpoko—since the divisions traditionally lived in separate village clusters and were only loosely confederated. European transcriptions of these names in places such as Chillicothe and Piqua, Ohio, Sewickley, Pennsylvania, and Pickaway, West Virginia, testify to some of these wanderings. Thus it was the Pekowi who began the Shawnee return to the Ohio Valley when they moved from eastern to western Pennsylvania in 1728. By 1750, some 1,200 Shawnee were living in villages along the Ohio River, from which they launched attacks against the Virginia frontier during the French and Indian War and Pontiac's Rebellion. Later they moved their villages to the Scioto River in southern Ohio, and after their defeat in Lord Dunmore's War they moved again to the Miami River headwaters in southwest Ohio. They consistently claimed Virginia west of the Alleghenies to be their hunting lands, along with most of Kentucky. They also denied the right of the Iroquois to dispose of this territory, as the Iroquois did in land sales to colonial governments in 1744 and 1768.

Under the influence of a nativist religious revival first preached by the Delaware prophet Neolin, Shawnees took the lead in defending the Ohio country from the white advance across the Appalachians in Western Virginia and Kentucky and also sent emissaries to other tribes to preach the necessity of Indian unity. These efforts suffered a temporary setback with the Shawnee defeat in Dunmore's War, but they continued during the American Revolution. During 1775—76, the Mequashake Shawnees led by Cornstalk adopted a neutralist position between the British and the rebel colonists, but members of other Shawnee bands formed war parties on their own or in concert with Mingos and militant Delawares. When Cornstalk was imprisoned and then murdered at Fort Randolph in 1777, the Mequashake joined the other bands in general warfare all along the frontier. White settlements along the Ohio, in the Kanawha Valley, and in Kentucky bore the brunt of these attacks, which continued through 1782, culminating in the famous second siege of Fort Henry at Wheeling in September of that year.

The Shawnees, along with other Indians resident in Ohio, were outraged when the British accepted Virginia's claim to the territory between the Great Lakes and the Ohio and ceded this territory to the United States in the 1783 Treaty of Paris, following the Revolution. Disputing the validity of the British cession, Shawnee militants urged the other Ohio tribes and also the Cherokees to fight on. Assaults on the frontier and on white settlers traveling the Ohio River multiplied after 1786 and continued into the early 1790s. Though Euro-American beachheads were established in 1788 north of the Ohio at Marietta and Cincinnati, native resistance succeeded in defeating armies sent against their villages in 1790 and 1791. Only after a combined force of regular troops and militia commanded by Gen. Anthony Wayne defeated a Shawnee-led Indian force at the Battle of Fallen Timbers in northwest Ohio in 1794 did the militants agree to give up their Ohio lands.

The Treaty of Greenville in 1795 cleared the way for white settlement on both banks of the Ohio and ended the threat of raids in what is now West Virginia. Even then, however, the militant Shawnee spirit remained unconquered. In the early 19th century, a new revitalization movement spread under the leadership of the prophet Tenskwatawa and his warrior brother Tecumseh. This movement was centered in new Shawnee villages in what is now Indiana and did not directly affect West Virginia.