Francisco de Orellana, a Spanish conquistador and explorer, founded the city of Guayaquil in 1538 while on his expeditions along the western coasts of South America. The area, strategically located on the banks of the Guayas River, was an attractive site for Spanish colonization due to its natural harbor and proximity to rich resources. The city was officially named Muy Noble y Muy Leal Ciudad de Santiago de Guayaquil, emphasizing its intended status as a loyal and noble city under Spanish rule. The establishment of Guayaquil marked a significant expansion of Spanish influence and control in the region, which had a considerable impact on local indigenous populations and the broader geopolitical landscape of South America at the time.

Orellana's venture was not merely for settlement; it was also a calculated move to secure trade routes in the Pacific, facilitating the flow of goods and resources from the Andes and inland areas to Europe. This foundation led to Guayaquil developing into a major port city that would serve as a hub for commerce and exploration, attracting settlers, merchants, and adventurers alike. Over the years, the city would grow and endure through various challenges, ultimately becoming an essential node in the Spanish colonial system.

The fusion of indigenous cultures and Spanish colonial governance began in earnest after Guayaquil's founding. The Spanish imposed their political, economic, and religious frameworks on the area, dramatically altering the social fabric and leading to both conflict and integration between different cultures. This change also set the stage for future events in South American politics, including eventual independence movements several centuries later.