Beginning with the first wave of European colonization, the religious discrimination, persecution, and violence toward the Indigenous peoples' native religions was systematically perpetrated by the European Christian colonists and settlers from the 15th-16th centuries onwards.

During the Age of Discovery and the following centuries, the Spanish and Portuguese colonial empires were the most active in attempting to convert the Indigenous peoples of the Americas to the Christian religion. Pope Alexander VI issued the Inter caetera bull in May 1493 that confirmed the lands claimed by the Kingdom of Spain, and mandated in exchange that the Indigenous peoples be converted to Catholic Christianity. During Columbus's second voyage, Benedictine friars accompanied him, along with twelve other priests. With the Spanish conquest of the Aztec empire, evangelization of the dense Indigenous populations was undertaken in what was called the "spiritual conquest." Several mendicant orders were involved in the early campaign to convert the Indigenous peoples. Franciscans and Dominicans learned Indigenous languages, such as Nahuatl, Mixtec, and Zapotec. One of the first schools for Indigenous peoples in Mexico was founded by Pedro de Gante in 1523. The friars aimed at converting Indigenous leaders, with the hope and expectation that their communities would follow suit. In densely populated regions, friars mobilized Indigenous communities to build churches, making the religious change visible; these churches and chapels were often in the same places as old temples, often using the same stones. "Native peoples exhibited a range of responses, from outright hostility to active embrace of the new religion." In central and southern Mexico where there was an existing Indigenous tradition of creating written texts, the friars taught Indigenous scribes to write their own languages in Latin letters. There is significant body of texts in Indigenous languages created by and for Indigenous peoples in their own communities for their own purposes. In frontier areas where there were no settled Indigenous populations, friars and Jesuits often created missions, bringing together dispersed Indigenous populations in communities supervised by the friars in order to more easily preach the gospel and ensure their adherence to the faith. These missions were established throughout the Spanish colonies which extended from the southwestern portions of current-day United States through Mexico and to Argentina and Chile.