A report by the bishopric of Nueva Galicia in 1572 stated that by that year, Chalchihuites consisted of only twenty Spaniards, including residents, merchants, and Franciscan missionaries. Its importance as a mining center increased when Spaniards and Tlaxcalteca indigenous people settled there by order of Viceroy Luis de Velasco in 1591.

Due to the geographical conditions of the region, six processing haciendas existed in the vicinity of the mining settlement, where silver and lead were processed. These conditions also favored irrigated agriculture and the production of orchards with fruit trees and vegetables.

Alongside the mining settlement, the towns of Nuestra Señora de la Asunción de Tlaxcala and San Francisco de Tonalá were founded, both administered by the Franciscans from the Chalchihuites convent. The San Francisco temple is one of the most important buildings at this point along the itinerary of the Royal Inland Road.

The San Francisco temple was originally a civil structure until 1583, when the convent was formally established. Inside this temple, notable figures include the Señor del Santo Entierro, which is believed to be a gift from Philip II, and the 17th-century polychrome sculpture of Nuestra Señora de las Aguas, whose devotion originates from Tlaxcala.