This was historically the territory of the Native American Wenrohronon and Eriehronon, who were driven out by the Seneca Nation in the Beaver Wars of the 1650s.

The Seneca controlled much of the territory of western New York as one of the nations of the powerful Iroquois Confederacy.

Many of the early arrivals were whites who settled on Native American land with the informal permission and toleration of tribal members.

They leased a portion of land, then mostly swamp, from the Seneca Nation to make their hub at what was developed as Salamanca.

At that time it was called the "town of Bucktooth", named after a notable Seneca who lived in the area.

According to the United States Census Bureau, the town has a total area of 18.4 square miles (47.6 km2), all land.

The Southern Tier Expressway (Interstate 86) runs through the Seneca reservation in the middle of the town.

On its west side, Salamanca forms a border with the towns of Coldspring and Napoli.