[2] It was established by the Franciscans on January 6, 1536[3] with the intention, as is generally accepted, of preparing Native American boys for eventual ordination to the Catholic priesthood.

[4][5] Students trained in the Colegio were important contributors to the work of Franciscan Bernardino de Sahagún in the creation of his monumental twelve-volume General History of the Things of New Spain, often referred to as the Florentine Codex.

The failure of the Colegio had long-lasting consequences, with scholar Robert Ricard saying that "[h]ad the College of Tlatelolco given the country even one [native] bishop, the history of the Mexican Church might have been profoundly changed.

While Bishop of Santo Domingo, Ramírez de Fuenleal had encouraged the Franciscans to teach the sons of Aztecs grammar in their native language of Nahuatl.

[7] Franciscan Arnaldo de Basccio began the task with considerable success, which gave support to the project of establishing an institute of higher learning.

[14] The establishment of such a school to train young men for the priesthood was highly controversial, with opposition especially coming from Dominican friars and articulated by the head of that order, Fray Domingo Betanzos.

[15][16] Franciscan Bernardino de Sahagún wrote a strong defense of the capacity of the Aztec, countering the opinions of those who doubted their ability not only to learn Latin grammar, but to speak, and compose in it.

[18] The original purpose of the Colegio was to educate a male indigenous priesthood, and so pupils were selected from the most prestigious families of the Aztec ruling class.

[22] Although there was great support from many sectors (excluding the Dominicans who objected to the founding of the Colegio), the physical structure was at first quite modest for lack of funds and later a stone house was built.

[23] The first sixty male students was a small cohort of sons of noble families; there was tremendous need for many more pupils, so the Franciscans actively recruited others from important towns in central Mexico, two or three boys 10 to 12 years of age.

A common eating area and sleeping quarters with beds being only a mat and a blanket placed on individual wooden platforms to keep pupils from the damp floor.

Spanish judge Alonso de Zorita, author of Life and Labor in Ancient Mexico: the Brief and Summary Relation of the Lords of New Spain[26] was aided by the translations of Pablo Nazareno, a former pupil at the Colegio.

According to Robert Ricard, the "error prevented the Church from striking deep roots in the nation, gave it the appearance and character of a foreign institution, and kept it dependent upon the mother country.