The Colegio de Santa Cruz de Tlatelolco, founded by Viceroy Antonio de Mendoza and Bishop Juan de Zumárraga, marked a pivotal moment in the educational landscape of the Americas. Located in Mexico City on the lands of the former Aztec empire, the school was established with a vision of providing comprehensive education to indigenous peoples, particularly those of noble lineage. This initiative stemmed from the broader colonial agenda of the Spanish Crown, which sought to integrate the indigenous population into European norms and practices while simultaneously converting them to Christianity.

The curriculum at Tlatelolco combined traditional European academic subjects such as theology, Latin, and philosophy with elements of indigenous culture and languages, particularly Nahuatl. This unique blend of knowledge aimed to empower native leaders who could serve as intermediaries between the Spanish authorities and the indigenous communities. The first students included sons of local chiefs, who studied alongside Spanish scholars and clergy. This confluence of cultures was notable as it represented one of the early attempts at intercultural education in the Americas.

The college produced some of the first books and writings in Nahuatl, including theological texts, which played a crucial role in the documentation and preservation of the language. This was particularly significant as the Spanish colonial period was often marked by the suppression of indigenous languages and cultures. The establishment of Tlatelolco laid the groundwork for future educational institutions in Latin America and sparked a series of intellectual exchanges that would influence both indigenous and European societies.