A number of explorers, such the Portuguese Cabral, Italian Vespucci and the Spaniards Magellan and Balboa, sail along the coast of South America after the arrival of Columbus in 1492. Portugal claims the colony of Brazil, while Spain takes the rest of South America. In fact, according to the Treaty of Tordesillas in 1494, the entire world was divided into half, Africa, Brazil and part of India going to Portugal, the rest going to Spain--nobody except Spain and Portugal paid much attention to the treaty.

Between 1531 and 1534, a Spanish army of conquistadores led by the adventurer Francisco Pizarro destroys the Inca Empire. Like the Aztecs, the Inca warriors, armed with slings, bows, spears and stone maces had difficulty coping with the Spanish soldiers, protected by metal armour, and using guns and horses. This picture of a Spanish horseman running down an Inca warrior was made near the time of the conquest. Also like the Aztecs, the Incas were weakened by civil war and disease. It is thought European-introduced disease killed Inca Huayna Capac and his successor Ninan Cuyachi in 1527. In the confusion, the sons of the Huayna Capac, Huascar and Atahualpa, fought to see who would be the next ruler. In 1532, Atahualpa was captured by a trick and murdered by Pizarro. In 1535, Pizarro founded a new Spanish capital city called Lima.

The Spanish appointed Huascar's brother Manco as the new Inca, but this proved a mistake on the part of Pizarro. Manco led a guerrilla resistance against the Spanish. This new war would last 36 years, and both Manco and Pizarro would be dead before it was over. Finally, in 1572, the last Inca, Tupac Amaru was captured and executed. Even so, in some remote mountain areas, Inca fighters still held out.

In 1544, the Spanish conquistadore Orellana crosses South America, starting in Peru and reaching the Atlantic Ocean, following the Marazon and Amazon rivers systems.

1510, the importation of African slaves to work mines and plantations in South America began. Although it was by no means the goal of the slave dealers and plantation owners, the mix of African, European and native peoples led to the creation a new and unique culture. This is especially visible today in Brazil.