The region around Antietam Creek had been home to Native Americans for thousands of years prior to settlement by Anglo-Europeans in the mid-18th century. Beginning in 1751 a certain John Wallace obtained several warrants for the land on which the center of the town now stands. In 1797 John Wallace, a son of the original British settler, laid out the town of Waynesburg in what was then the state of Pennsylvania in the United States. When incorporated in 1831, the borough was given the name "Waynesboro." It is one of several dozen towns, cities, and counties named after General Anthony Wayne, a hero of the American Revolutionary War.