The town is reportedly named after King Louis XIV of France, but is pronounced as "Lewis-ville."

The Town of Louisville is at the northern border of the county and is west of Village of Massena.

Nahum Wilson, originally from Peru, NY, and his family were the first to settle the area in April 1800.

Early settlers frequently interacted with their Canadian neighbours (then British North America) and both would often cross the St. Lawrence River to meet.

During the War of 1812, although they still had good relations with their neighbours, the men of Louisville formed a militia and elected Benjamin Daniels as their "high sergeant".

The northern town line, which is delineated by the St. Lawrence River, is the international border with Canada, specifically the Province of Ontario.

New York State Route 37B diverges northward from NY-37 near the eastern town line.