For over a hundred years, the Spanish and the Portuguese dominated settlement in the New World. The first English colony was founded at Roanoke (in what is now North Carolina) in 1585. After a three-year loss of contact with England, the settlers were found to have disappeared; their fate remains a mystery. The colony of Virginia, founded by a private company of investors at Jamestown in 1607, also struggled in its first years and relied on food from the Powhatan Confederacy. Over time, the colony gained a steady hold by producing tobacco for a growing European market.

Settlement on the coast of New England was undertaken for different reasons. There, radical Protestants sought to escape Anglican repression in England and begin new lives. The small and struggling outpost of Plymouth (1620), founded by the Pilgrims who arrived on the Mayflower, was followed by Massachusetts (1630), a colony of Puritans that grew into a prosperous settlement.

Whereas the Spanish conquered indigenous empires and established large-scale dominance over Mexico and Peru, English settlements merely hugged the Atlantic coastline. This did not prevent conflict with the indigenous inhabitants over land and resources, however. At Jamestown, for example, English expansion undermined prior cooperation with the Powhatan Confederacy; disease and warfare with the English led to drastic population losses among the Powhatans.

French navigator and explorer Samuel de Champlain founded the first permanent French settlement, at Quebec, in 1608. Ville-Marie, latter-day Montreal, was founded in 1642. Following the waterways of the St. Lawrence, the Great Lakes, and the Mississippi, the French ventured into much of modern-day Canada and at least thirty-five of the fifty states of the United States. French traders forged relations with the Huron Confederacy, a league of four indigenous nations that dominated a large region north of Lake Erie, as a means of gaining access to hunting grounds and trade routes for beaver and other animals. In 1682, French explorer René-Robert Cavelier LaSalle descended the Mississippi to the Gulf of Mexico, opening the way for French occupation of Louisiana.

While establishing their foothold in the north, the French slowly acquired new territories in the West Indies, including Cayenne (1604), St. Christophe (1625), Martinique, Guadeloupe, and Saint-Domingue (1697) on the western side of the island of Hispaniola. These islands became centers of tobacco and then sugar production. French ambitions on the mainland and in the Caribbean sparked a century-long competition with the English.

European involvement in the Americas led to the profound transformation of pre-existing indigenous societies and the rise of a transatlantic slave trade. It also led to an acceleration of global trade and cultural exchange. Over time, the combination of indigenous, European, and African cultures gave birth to new societies in the New World. In turn, the profits of trade and the impact of cultural exchange greatly influenced European society.