The Franciscan order had a prolific presence in various parts of New Spain, particularly in what is now the state of Zacatecas. On January 12, 1707, Fray Antonio Margil de Jesús, along with ten other Franciscans, founded the College of Our Lady of Guadalupe de Propaganda Fide on the outskirts of Zacatecas. This institution interacted with its counterpart in Santa Cruz de Querétaro along the Camino Real de Tierra Adentro. Construction took place between 1713 and 1717, overseen by Father Guardian José Guerra.

The plains of the Teocaltiche Valley, an area of Chichimeca towns, were an important crossing point for communication routes between Zacatecas and Mexico City and Guadalajara. This facilitated the emergence of a successful agricultural and livestock economy. The Altos de Jalisco soon became, along with Aguascalientes, suppliers to the mining settlements in the north, leading to the founding in 1760 of the town of Nuestra Señora de la Encarnación de los Macías, at the former post of El Sauz.

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.

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.

Located in the municipality of Tepotzotlán, State of Mexico, the ancient Conciliar College and Seminary of San Francisco Javier, of the Society of Jesus, was for many generations a pilgrimage site for the Chichimeca until the formal establishment of the independent lordship of Tepotzotlán in 1460 during the 15th century.