The Villa Protectora de San Miguel el Grande and Sanctuary of Jesús Nazareno de Atotonilco is located in the north-central region of Guanajuato, which before the arrival of the Spanish was occupied by Chichimec Indians extending from Chamacuero to Guanajuato and San Felipe. The first contacts between the natives and the Spanish occurred in the 1520s, but colonization would not take place until 1542.

The town of San Juan del Río was founded in the first half of the 16th century, as part of the jurisdiction of the mayor's office of Querétaro. It gained importance following the territorial appropriation of the Bajío region by the Spanish, becoming a significant enclave for access to northern New Spain.