Pedro de Valdivia, a Spanish conquistador, founded Santiago in the central valley of Chile while seeking to expand Spanish territories in South America. After receiving a royal commission and initial explorations of the region, he sought a site that would serve as a strategic location for military and economic endeavors. The chosen site, near the Mapocho River and surrounded by mountains, offered fertile land ideal for agriculture and herding, aligning with the Spanish interests of resource extraction. On February 12, 1541, Valdivia laid the city’s cornerstone, marking the establishment of Santiago del Nuevo Extremo, later simplified to Santiago. The foundation of Santiago was not merely a military fortification; it aimed to facilitate the assimilation of local indigenous populations and bolster Spanish influence in the region. The name 'Santiago' pays homage to Saint James, the patron saint of Spain, indicating the religious significance of Spanish conquests.

Following its foundation, Santiago faced early challenges, primarily from the indigenous Mapuche population, who resisted Spanish incursions into their territory. Valdivia's initial successes led to the establishment of trade and the spread of Spanish customs, but the struggles against the Mapuche warriors would continue for years, complicating the colonial efforts. Santiago quickly grew into a hub for Spanish governance in the region, attracting settlers and becoming a focal point for subsequent conquests into what is now Chile. Its layout combined urban organization with Spanish architectural styles, establishing a legacy that would influence future urban developments in Latin America. Over the subsequent decades, Santiago would emerge as an important administrative and military center, enabling the further exploration and colonization of Chilean territory.