Lewis Wetzel, frontiersman, scout, and Indian fighter, was born in August 1763. He may have been born in Lancaster County, Pennsylvania, where his parents lived for several years, or along the South Branch of the Potomac, in the present Eastern Panhandle. The Wetzel family settled along Wheeling Creek, in what is now Ohio County, in 1769, along with the Zane, McColloch, and allied families.

Wetzel developed an early hatred for Indians when he and his brother, Jacob, were captured by Wyandots in 1778 while tending corn at the family homestead. In resisting, Wetzel received a gunshot wound, a superficial grazing of his breastbone. After two days in captivity, the brothers escaped and returned to Wheeling. Wetzel, his father, and brothers were among the defenders of Fort Henry when it was attacked by British and Indian forces in September 1782.

On June 19, 1786, Wetzel's father, John, and his brother, George, were killed by Indians and his brother, Martin, was wounded while on a hunting trip. Wetzel himself was the only member of the party unhurt. This experience led him to undertake a private war on all Indians. His most notorious murder was of the Seneca chief Tegunteh, who was peacefully involved in the negotiation of the Treaty of Fort Harmar (1789), near present Marietta, Ohio. Wetzel was twice arrested for this crime but never punished. He later claimed to have taken 27 scalps, but it is likely that the number of his victims was considerably higher. It is asserted that Wetzel could reload his rifle while running, a rare feat among frontiersmen that enabled him to stop and fire while being pursued.

After the peace that followed the signing of the Treaty of Greenville (1795), Wetzel moved to Louisiana Territory, where he was imprisoned in New Orleans for several years on conviction of counterfeiting. He died at Rosetta, near Natchez, Mississippi Territory, in 1808. His body was later reinterred at McCreary Cemetery near Wheeling. Wetzel County was named for Lewis Wetzel.

Lewis Wetzel's role in frontier history was romanticized in the early novels of Zane Grey. More recently his exploits have been recounted in the works of Allan W. Eckert, especially That Dark and Bloody River.