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But not until the Spanish conquest of Peru was the conquest of the Aztecs matched in scope by the victory over the Inca empire in 1532.

A second (and permanent) settlement was established in 1580 by Juan de Garay, who arrived by sailing down the Paraná River from Asunción (now the capital of Paraguay). He dubbed the settlement "Santísima Trinidad" and its port became "Puerto de Santa María de los Buenos Aires." The city came to be the head of the Governorate of the Río de la Plata and in 1776 elevated to be the capital of the new Viceroyalty of the Río de la Plata.

Spain's administration of its colonies in the Americas was divided into the Viceroyalty of New Spain 1535 (capital, México City), and the Viceroyalty of Peru 1542 (capital, Lima). In the 18th century the additional Viceroyalty of New Granada 1717 (capital, Bogotá), and Viceroyalty of Rio de la Plata 1776 (capital, Buenos Aires) were established from portions of the Viceroyalty of Peru.

During the Napoleonic Peninsular War in Europe between France and Spain, assemblies called juntas were established to rule in the name of Ferdinand VII of Spain

The Libertadores (Spanish and Portuguese for "Liberators") were the principal leaders of the Spanish American wars of independence. They were predominantly criollos (Americas-born people of European ancestry, mostly Spanish or Portuguese), bourgeois and influenced by liberalism and in some cases with military training in the mother country.

These began a movement for colonial independence that spread to Spain's other colonies in the Americas. The ideas from the French and the American Revolution influenced the efforts. All of the colonies, except Cuba and Puerto Rico, attained independence by the 1820s

In 1898, the United States won victory in the Spanish–American War from Spain, ending the Spanish colonial era

It has been estimated that in the 16th century about 240,000 Spaniards emigrated to the Americas, and in the 17th century about 500,000, predominantly to Mexico and Peru.

The population of the Native Amerindian population in Mexico declined by an estimated 90% (reduced to 1–2.5 million people) by the early 17th century. In Peru the indigenous Amerindian pre-contact population of around 6.5 million declined to 1 million by the early 17th century.[citation needed] The overwhelming cause of decline in both Mexico and Peru was infectious diseases.

The Spaniards were committed, by Royal decree, to convert their New World indigenous subjects to Catholicism. However, often initial efforts were questionably successful, as the indigenous people added Catholicism into their longstanding traditional ceremonies and beliefs. The many native expressions, forms, practices, and items of art could be considered idolatry and prohibited or destroyed by Spanish missionaries, military and civilians. This included religious items, sculptures and jewelry made of gold or silver, which were melted down before shipment to Spain.