Old Greenville on the St. Francis River was shaped by a long human presence, early settlement, wartime disruption, industrial growth, and eventual relocation. For thousands of years before European-American settlement, various Native American groups used the area's land, forest, and river resources, and archaeologists identify brief prehistoric occupation here during the Dalton, Archaic, Woodland, and Mississippian periods, with the small archaeological sites likely representing temporary hunting, fishing, or gathering camps near a ford on the Natchitoches Trace. In the early 1800s Isaac Kelley moved to the site and applied for a Spanish land grant, and in 1806 Dr. Elijah Bettis Sr. and his family arrived and helped develop the community, which was first known as Bettis' Ferry until 1818, when it was renamed Greenville in honor of the 1794 Treaty of Greenville; with Wayne County established that same year, Greenville became county seat of a vast area. After the Civil War, the town experienced its greatest growth as the timber industry expanded and the railroad arrived; in 1892 Hiram Holladay brought the railroad to Old Greenville and, with Eli Klotz, built a large sawmill and planing mill that employed hundreds, helping the town reach a peak population of 1,051 with 125 businesses before a dwindling timber supply and Holladay's death in 1899 brought rapid decline. Wayne County was devastated during the Civil War, and Old Greenville was occupied by both Union and Confederate forces; on July 20, 1862, about 300 Confederate troops surprised and routed members of the Twelfth Regiment Cavalry, Missouri State Militia, plundering their camp and supplies before Union troops reoccupied Greenville that evening. In the 20th century, more than 500 Wayne County soldiers served in World War I, and a Statue of Liberty scale model erected at the courthouse in 1917 to honor the county's 30 war dead was moved in 1948 to the courthouse in the new town by members of the American Legion. Old Greenville was not severely affected by the Great Depression because it could produce needed food and supplies locally, though Works Progress Administration labor provided supplemental income and built some of the sidewalks that remain. Repeated flooding of the St. Francis River, with major floods recorded in 1826, 1844, 1863, 1904, 1908, 1915, and 1935, led to national flood-control efforts, the construction of Wappapello Dam from 1938 to 1941, and the completion of the move of Greenville in 1941 to a new site two miles northeast, leaving behind the sidewalks and foundations of a town that had existed for nearly 150 years.