San Juan del Rio marked, along with Santiago de Querétaro, a safeguard border during the confrontation between the Chichimeca groups called barbarians and the viceregal expansionism; Later on, both cities were the intermediate point between mining farms of Zacatecas and San Luis Potosí with Mexico City.

The Camino Real de Tierra Adentro, also known as the Camino a Santa Fe, was a 2560-kilometer-long commercial route that ran from Mexico City to the city of Santa Fe, New Mexico, USA. UU actively from the mid-sixteenth century until the nineteenth century.