St. Marys was first established in the early 1840s on the banks of the Thames River and Trout Creek. The river water fell over a series of limestone ledges making 'Little Falls', an early nickname for St. Marys. The falls gave power for the pioneer mills to make flour from grain grown in the area.

St. Marys was integrated into the province of Ontario, officially, in 1863. Yet, it did not incorporate itself into Perth County. For administrative purposes, it is treated to be within Perth County, but technically the town resides in St. Marys County.

With the arrival of the Grand Trunk Railway in the late 1850s St. Marys became a center for milling, grain-trading and the manufacture of agriculture-related products. The railway linked the town to the rest of the world and wrapped the local landscape with its two large trestle bridges on limestone pillars across the waterways.