[5] In the Mississippian period, Dupo was the site of one of several multi-mound communities in the floodplain near Cahokia.

[8] The French village of Prairie du Pont was first settled around 1750 by townspeople moving out of Cahokia.

It was located at a bridge over what is now known as Prairie du Pont Creek, on the trail from Cahokia to Kaskaskia, which was the first wagon road in Illinois.

[9] The settlement may have been motivated by Dupo being located 10–12 feet higher than Cahokia and thus being more protected from floods on the Mississippi River.

[10] The village's growth was further spurred by the prominent local citizen Antoine Girardin, who parceled off parts of the Cahokia commons to residents of Prairie du Pont.

[11] The early French village at Prairie du Pont followed a tripartite system of land ownership that was common in the Illinois country: private houses in a row, "common fields" enclosed by a shared fence but divided into narrow strips owned and farmed by a particular family, and the actual commons used jointly by the inhabitants for grazing their livestock.

[13] Among the early inhabitants of Prairie du Pont was the noted gunsmith Philip Creamer, who settled in the area in 1805.

[10] Some parts of the historic Prairie du Pont community, such as the Pierre Martin House, are now located in unincorporated North Dupo, Illinois.

A Prairie du Pont school district was established by legislative enactment in 1847, to be funded by leases of the village commons, but no school was actually held in the village until 1861, due to inadequate funds.

[17] However, the oil boom was short-lived and the economy of the town returned to depending primarily on the rail yard.

[17] In 1997, the town considered switching its name back to Prairie Du Pont to put the industrial period behind it and better attract tourism, but ultimately left its name unchanged.

[18] The crash was caused by a 1.5 miles (2.4 km)-long freight train breaking in half and the two halves then colliding.