The Colegio de Guadalupe was built on the "Huertas de Melgar", land named after Jerónima de Castilla, the widow of Melgar, who donated it in 1674. On this site stood an old hermitage dedicated to Our Lady of Mount Carmel. Two years later, ecclesiastical permission was granted to construct a new sanctuary dedicated to the Virgin of Guadalupe, along with a guesthouse for friars traveling northward.

The initial construction work began in 1702 and included the lower level of the complex: the Cloister of Saint Francis, the church and its sacristy, the atrium, a cemetery for benefactors, and the novitiate. On January 12, 1707, these foundations gave rise to the Apostolic College of Propaganda Fide of Guadalupe, Zacatecas. The building efforts continued, and by 1797 the atrium’s 14 Stations of the Cross had been completed, each with a niche marked by a stone cross. These stations commemorate the path Christ followed to Calvary, where he was crucified.

The church’s façade was constructed in the first half of the 18th century and reflects the economic prosperity enjoyed by some in the region at that time. The elaborate ornamentation and the use of twisted Solomonic columns are clear expressions of the Baroque style.