The migration of peoples to the New World led to an exchange of animals, plants, and disease, a complex process known as the Columbian exchange. Columbus had brought sugar plants on his second voyage; Spaniards also introduced rice and bananas from the Canary Islands, and the Portuguese carried these items to Brazil. Everywhere they settled, the Spanish and Portuguese brought and raised wheat. Grapes and olives brought over from Spain did well in parts of Peru and Chile.

Apart from wild turkeys and game, Native Americans had no animals for food. They did not domesticate animals for travel or use as beasts of burden, except for alpacas and llamas in the Inca Empire. On his second voyage in 1493, Columbus introduced horses, cattle, sheep, dogs, pigs, chickens, and goats. The horse enabled the Spanish conquerors and native populations to travel faster and farther and to transport heavy loads. In turn, Europeans returned home with many food crops that became central elements of their diet.

Disease brought by European people and animals was perhaps the most important form of exchange. The wave of catastrophic epidemic disease that swept the Western Hemisphere after 1492 can be seen as an extension of the swath of devastation wreaked by the Black Death in the 1300s, first in Asia and then in Europe. The world after Columbus was thus unified by disease as well as by trade and colonization.