Long before white settlers entered the area, Adena and Hopewell Indians inhabited the area of Fredericktown. Early settlers found three mounds and earthworks located on nearby hilltops. While the Raleigh Mound and Stackhouse Mound and Works are preserved today, the third mound, located by what is presently the Baptist Church, was demolished. Both preserved mounds were most likely ceremonial structures and they are oriented towards the Sun's movements. When settlers arrived, the sites were abandoned with few other traces of the Natives who lived there. There were a few scattered Native Americans living nearby along what was then the periphery of Indian Lands established by the Greenville Treaty Line.
The first white settler was John Kerr who in 1807 bought and planned the town, and built a mill on the North Branch of the Kokosing River. Growth was sluggish until the Sandusky, Mansfield, and Newark Railroad came through the village in 1853. A grain elevator, foundry, and other small trading businesses were built, helping to establish Fredericktown more firmly as the local business center than the nearby crossroad settlements of Batemantown, Waterford, and Ankeneytown. Around World War II a small airplane paneling factory was built and later reverted to furniture manufacturing. In the last half of the 20th century, a few light manufacturing operations and the largest privately owned general construction contractor in Ohio, Kokosing Construction , were established.