The San Miguel River, or La Laja, flowed nearly five kilometers from the Villa de San Miguel el Grande, now San Miguel de Allende. During the 16th, 17th, and 18th centuries, crossing this tumultuous river had to be done using canoes or through the various bridges constructed in the jurisdiction during that time.

The old Hospital of San Juan de Dios in the city of San Miguel de Allende, Guanajuato, also known as the Royal Hospital, is a work attributed to Father Juan Manuel de Villegas, who was in charge of its construction in 1753.

The evangelization of the Bajío undertaken by the Franciscans began in Jilotepec, with the support of the Otomi people. They founded numerous indigenous towns, which later became Spanish settlements. These places are now part of the Royal Inland Road as it passes through the present-day state of Guanajuato.

In 1529, a group of families belonging to an Otomi population called Nopala, who lived in the province of Jilotepec, set out for the area of La Cañada, in what is now the state of Querétaro. This area was inhabited by Chichimeca groups with whom the native leader of the group, named Conín, maintained a friendship and exchanged animal skins that the locals traded for salt and grains.

During the 16th century, the Spanish crown attempted to populate the territory of the former encomienda of Jilotepec, located on the Chichimeca frontier. This effort aimed to protect the road leading from Mexico City to the northern territories of New Spain.

The Hacienda de Chichimequillas is located in the municipality of El Marqués, Querétaro. It was built around 1690 by Carmelite monks who settled in the area to assist and settle the Chichimeca Jonaces and Pame indigenous people, while also providing shelter to travelers journeying along the Camino Real de Tierra Adentro to and from the mining regions of Guanajuato and Zacatecas.

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.

The stretch between the Puente de La Colmena and the Ex Hacienda de la Cañada connected the towns of Tepeji del Río and Jilotepec and still retains both the original route layout and the cobblestone pavement made of round stones. This 3.5 km long route is flanked by small stone walls and large pirules (a type of tree).

During the colonial era, the current territory of the state of Hidalgo was of great importance due to its missionary activity. Several churches and convents were founded in what was called the Province of the Holy Gospel, which were under the jurisdiction of the Archdiocese of Mexico. The extensive missionary activity began in the pre-Hispanic center of Tula, led by the Franciscans, the first order to arrive in the province. Additionally, the first significant mines near Mexico City were discovered in the state of Hidalgo.

During the early stages of the northward expansion into what would become New Spain, specifically between the 1520s and 1540s, the town of Aculco and its surroundings were a significant transit area for colonizers and missionaries. For this reason, this part of the Royal Inland Road was referred to as the "Gate of Tierra Adentro," through which the regular movement of merchants, officials, ranchers, and livestock took place.