Prior to 1730, Native Americans were the only known occupants of the territory now known as Wayne County. Settlers trickled into the territory, occupying land along the Neuse River. There was no general migration here until after 1750; as populations built up in the coastal areas, some settlers moved west for land.
Wayne County was established during the American Revolutionary War on November 2, 1779 from the western part of Dobbs County. It was named for "Mad Anthony" Wayne, a general in the war. The act establishing the County provided that the first court should be held at the home of Josiah Sasser, at which time the justices were to decide on a place for all subsequent courts until a courthouse could be erected. By 1782 the commissioners were named. In 1787 an act was passed establishing Waynesborough on the west side of the Neuse River, on the land of Doctor Andrew Bass. The courthouse was built here.
In 1855 parts of Wayne County, Edgecombe County, Johnston County, and Nash County were combined to form Wilson County.