The county was named for Mad Anthony Wayne whose military career had made him a well-known hero.

When he surprised the British garrison at Stony Point on July 15, 1779, he acquired the nickname "Mad" Anthony.

The 1805 Act divided the half million acres (2,000 km2) of Wayne County, formed the Tallassee Strip, and set the stage for the land lottery that would result in more formal settlement of the area.

On December 8, 1806, the Georgia General Assembly created appointed five commissioners to establish a permanent site for a county seat and called for county court to be held at the home of one those commissioners, Roberta Smallwood, until a permanent site could be established.

Its exact location remains a mystery although it is known it was 9 miles north of Waynesville on the Post Road near the ford of Buffalo Swamp.

In December 1847, the General Assembly called for another set of commissioners to select a county seat near the home of William Flowers near the ford of the Buffalo Swamp.

The law also called for county court to be held at the courthouse then in existence near the residence of James Rawlinson.

Ambling along as Station Number 6 on the Atlantic and Gulf Railroad, the town grew into a city primarily due to the efforts of its first mayor, Willis Clary.

Clary is credited with convincing the Macon and Brunswick Railroad to locate its tracks so that they crossed the Atlantic and Gulf rails at Jesup.

The rail line connected Screven and Thomasville which at the time was a resort city popular with Europeans and wealthy Americans.

Rail access made it easier for Odum's turpentine and sawmills products to be shipped to larger markets.

Through the years, pine tree by-products like turpentine and naval stores made communities, schools and churches spring up along the paths of the railroads and the streams and creeks.

Places like Mount Pleasant, Gardi, McKinnon, Doctortown, Manningtown, Brentwood, Ritch, O'Quinn, Madray Springs and Piney Grove were centers of family life.

[12] The northern and eastern two-thirds of Wayne County, from north of Odum to south and east of Screven, is located in the Altamaha River sub-basin of the basin by the same name.