The city is surrounded on three sides (east, west, and south) by the easternmost parcel of the Mark Twain National Forest.

The earliest beginnings of Fredericktown occurred around 1715 when local Indians guided French explorers to the area, which at that time was part of Upper Louisiana, in order to show them sources of lead which the French had hoped would also contain silver.

The French governor of Louisiana, Antoine Laumet de La Mothe, sieur de Cadillac, failed to find silver, but succeeded in recruiting other French investors in the Company of the West, organized in 1717, to exploit the mineral resources of Louisiana.

[7] The earliest European settlement in the area near what is now Fredericktown was Mine La Motte, a small community about 6 miles (10 km) to the north.

The need for a local source of lead for ammunition made Mine La Motte one of the earliest European settlements in the interior of the North American continent.

Another earlier settlement was the French Catholic community of Saint Michel, which is located just north of the current Fredericktown site on the other side of Saline Creek.

[8] At the time that Madison County was organized, the land south of Saline Creek was owned by Col. Nathaniel Cook.

[10] On October 30, 2024, the Critical Mineral Recovery (CMR) battery plant experienced a fire, causing explosions within the building.

[11] Two days after the fire, thousands of dead fish were found along 2.5 mile stretches of Village Creek and St. Francis River, believed to be killed by PFAS ingredients in firefighting foam.

[13] The Fredericktown Courthouse Square Historic District, Fredericktown Missouri Pacific Railroad Depot, Fredericktown United States Post Office, Madison County Courthouse, and St. Louis, Iron Mountain and Southern Railroad Depot are listed on the National Register of Historic Places.

The St. Francis River, at the base of Black Mountain, is approximately 540 feet above sea level.

Fredericktown is nearly unique in the United States for the variety of minerals and metals that have been found and commercially mined nearby, including lead, iron, copper, silver, cobalt, nickel, zinc, tungsten, and small amounts of gold, all of which have been mined at various times within 20 miles (32 km) of the town.

Examples of the minerals that were once mined can still be found in the abundant tailings on the south side of the St. Francis River, just downstream of a now-breached stone dam.

They consist of metallic-appearing sulfides such as sphalerite, arsenopyrite, and marcasite embedded in opaque veins of quartz.

Careful searchers can also find crystals of wolframite, a tungsten ore that was mined briefly during World War II when access to other sources was cut off, and small grains of topaz, which caused the earlier silver miners of the area considerable economic grief by wearing out their diamond-tipped drills more quickly than anticipated.

Madison County also contains unique igneous rocks not found anywhere else, such as Devonite Archived June 8, 2011, at the Wayback Machine, a colorful decorative stone found only in a single igneous intrusion dike on Mount Devon.