Indigenous allies were crucial to the Spanish success in Latin America. Both Cortés and Pizarro formed alliances with local tribes who were enemies or rivals of the Aztec and Inca empires, respectively. These indigenous groups provided the Spaniards with manpower, local knowledge, and strategic support. For instance, Cortés allied with the Tlaxcalans, who were fierce enemies of the Aztecs and provided thousands of warriors to assist in the siege of Tenochtitlán. Similarly, Pizarro leveraged rivalries within Andean societies to dismantle Inca authority. These alliances were not solely military but also provided cultural insights, which the Spanish used to manipulate local politics and establish their dominion.

While there were similarities in the Spanish approach to the conquest of both the Aztec and Inca empires, including the use of military technology and alliances with rival indigenous groups, there were also distinct differences. Against the Aztecs, Cortés relied heavily on the formation of alliances with discontented vassal states and exploited the political unrest within the Aztec Empire. In contrast, Pizarro's conquest of the Incas was significantly facilitated by the recent civil war between Atahualpa and Huáscar, which left the empire divided and weakened. Pizarro also made strategic use of the capture of the Inca emperor to command authority, whereas Cortés had to navigate the more complex political environment of the Aztec capital Tenochtitlán.

The introduction of European diseases like smallpox, measles, and influenza had a catastrophic impact on indigenous populations in Latin America, causing widespread mortality and disrupting societal structures. These diseases preceded conquistadors in many areas, creating chaos and weakening the social fabric. High mortality rates, particularly among the elite classes who were more engaged in interactions with the Europeans and thus more exposed to their diseases, led to power vacuums and succession crises within indigenous societies. In the Aztec and Inca empires, the deaths of leaders and nobles contributed to internal instability, making it easier for the Spanish to impose their rule. The psychological impact of the epidemics also cannot be understated; many indigenous people viewed the diseases as supernatural signs of the Spaniards' power, further undermining resistance to the conquests.

Interpreters played a pivotal role in the Spanish conquest of the Americas, often serving as the only means of communication between the Spaniards and indigenous peoples. Malintzin, also known as La Malinche, was a Nahua woman who became a key figure in Hernán Cortés' conquest of the Aztec Empire. Her linguistic skills (she spoke both Nahuatl and Maya, and quickly learned Spanish) were indispensable for negotiation and alliance-building. More than just a translator, Malintzin provided Cortés with intelligence and strategic advice, significantly influencing the course of the conquest. Her role underscores the complexity of cultural interactions during this period and the nuanced role individuals played in facilitating the sweeping changes that followed.

The Spanish invoked the concept of a 'just war', as outlined by theologians like Saint Augustine, which argued that conquest was acceptable if it was done to spread Christianity and save pagan souls. This rationale was codified in the 'Requerimiento', a declaration read by Spanish conquistadors to indigenous peoples that demanded their submission to the Church and the Spanish crown. The document stated that refusal to comply would justify war against them under the guise of saving their souls. Additionally, the Papal Bull 'Inter Caetera' issued by Pope Alexander VI in 1493 granted Spain the right to conquer lands in the Americas, which the Church considered heathen, thereby providing a divine sanction for the Spanish conquests.