The first sustained contacts between Europeans and the indigenous peoples of North America began early in the sixteenth century. The Portuguese had established their presence on the coast of Newfoundland and in the offshore fisheries by 1506, when they began to pay duties to their government on the Newfoundland catches. In the same year, seven captives were brought from North America to France in a vessel from Rouen. The Beothuk of Newfoundland were one of the earliest First Nations groups to be hit by European disease. They were also one of the most deeply affected groups; a combination of European epidemics, which swept through their population, played a major role in the extinction of this Nation. In 1535 Jacques Cartier had established Sainte Croix, in the territory of the Laurentian Iroquois, and within 65 years diseases borne by the Europeans had destroyed the population of Iroquois, although they were not eliminated as the Beothuk had been.

The Spanish moved north from New Spain, or Mesoamerica, in search of gold. Throughout the sixteenth century they explored territory and conquered nations in Florida and the south-west of what is now the United States. The French were also active in this area, and competed with the Spanish for dominance. For the English, the attempted settlement of Walter Raleigh on Roanoke Island, off the Atlantic coast, ultimately failed to establish a permanent foothold in the New World. Although these initial explorations and settlements did not involve significantly large numbers of Europeans, they did have a great deal of impact upon First Nations and Native American groups. The Spanish and French colonisers fought wars with indigenous groups, killing many. They also encouraged warfare between groups, and introduced and spread numerous European diseases that greatly impacted the population. Indigenous peoples suffered a marked demographic decline, little of which was the direct result of organised European military activity. The continual exposure to contagious and devastating diseases such as smallpox and measles had far more impact, resulting in the destruction of entire populations. These diseases would spread beyond the European territories by means of well-established trade routes between societies. A general decline in the quality of life resulted in increasing mortality and, at the same time, decreasing fertility. The increasing pressure caused by European migrants forced many indigenous people to accept a poor diet, unsuitable and unfamiliar housing, and, in some instances, hard labour for colonists. This in turn caused stress, low immunity to disease, and miscarriage. In general, all regions of North America saw a slow initial period of decline in the native population during the sixteenth and early seventeenth century. This was followed by much more rapid decrease during the late seventeenth century through to the nineteenth century. The indigenous populations reached their lowest numbers in the early 1900s, after which they began to slowly increase once more.

Spanish ambitions in the New World took a more aggressive and invasive approach than those of the European nations involved in settling more northern areas. In 1526 a group of five hundred soldiers, settlers, and enslaved Africans founded the settlement of San Miguel de Guadeloupe. Their expedition was spectacularly unsuccessful; the 150 survivors were evacuated within a few months. Two years later, Panfilo de Narvaez led a similarly doomed expedition. He and his army of four hundred voyaged to south Florida. Along the way they transmitted an unknown pathogen to the Native Americans of Texas, resulting in the deaths of approximately half of the population. The 1540s saw a series of Spanish expeditions into the interior of the North American continent. Vasquez de Coronado led a force from the Pueblo region into Kansas and the Great Plains. They attacked pueblo communities, and further advanced the spread of European diseases amongst indigenous populations. Hernando de Soto’s travels into the interior took a far more aggressive form. He and his soldiers systematically destroyed Amerindian communities and tortured their inhabitants. He was obsessed with finding gold, and was brutally harsh in the treatment of those who stood in his way. During the 1540s two permanent settlements were founded; Saint Augustine and San Juan.

Because of the predominance of unattached males in the settler population of the Spanish, a substantial mestizo population arose. They were the offspring of Spanish men and indigenous women. In the French territories of the north, a population of mixed French and Amerindian descent arose through the expansion of the fur trade in North America. Many European traders married indigenous women, and the resulting populations in both Spanish and French areas found themselves in a unique position between two dissimilar worlds.

The continuing push for more and more farmland meant that the Europeans on the Atlantic coast and the Saint Lawrence valley regions gradually pushed indigenous groups further to the west. The settlers employed several methods in forcing First Nations to relinquish their land. The expansion of the European population into the best farmlands often simply shoved former inhabitants to one side, leaving them to migrate to wherever there was space to accommodate them. If the indigenous people resisted this expansion, it often meant that war would be waged. The Europeans virtually always emerged victorious, due to their advanced military technology. As the Europeans pushed further inland, it was often the emerging governments of the New World who would step in to remove the First Nations or Native Americans to a more convenient location. It was in this manner that many groups were confined to reservations or forced to migrate west of the Mississippi.

The colonies of the New World were an ideal place for demographic expansion of the European population. Europeans found that the climate of present-day Canada and the United States could be harsh, but was relatively easily adapted to. Unlike the Caribbean, which proved to be more than the European constitution could handle, more northern latitudes were somewhat similar to Europe. It was not long before Europeans introduced Old World plants and animals with success, allowing them to further adapt to North America.

The growing European population followed a general pattern in its establishment. After the initial stages of exploration and occupation, the first wave of European settlers was usually young, single men. These men soon established themselves, sending for their friends and families. Perhaps more importantly, word of their success spread throughout their home countries, encouraging more emigrants. Later migrants were often family groups travelling together, generally to rural areas, and in later stages of settlement immigrants began arriving in North American cities and staying there to work in the urban environment.

Population growth varied from region to region. For example, even after Britain had gained control of France’s New World colonies, the French population remained significant. This was in spite of the fact that immigration from France was virtually non-existent; a high rate of natural increase kept the population booming. New World populations could expand in a number of ways. Regions might continue to receive numerous immigrants directly from Europe. A high birth rate might keep a population expanding, even when there was little immigration. As time went on, internal immigration became more of a factor. Areas in the west of the continent often received many immigrants of European descent who had been born in the New World, and who migrated from east to west.

Between 1790 and 1810 the growth rate of the American population was a staggering 35 per cent per decade. This was due both to natural increase and to continued immigration. Approximately 150,000 new migrants arrived in the United States during this period. The total population of the U.S. was estimated at 7,224,000 in 1810, while Canada's was approximately 460,000. By 1830 the American population of European descent was 12,901,000, and Canada’s was approximately 920,000.

In 1861 the population of non-First Nations origins in Canada was 3,250,000. The preceding decade had seen the population rise by 641,000 due to natural increase, and by 152,000 due to continuing immigration. The population was distributed along the Saint Lawrence River, in the Maritime provinces, and on the southern end of Vancouver Island. At the same time, the population of the United States was thirty-one million, of which 2.5 million were immigrants who had arrived during the preceding decade. There were also 448,070 free Africans living in the United States at this time. The population tended to be largely rural, as was the case in Canada. Less than 20 per cent lived in settlements of more than 2,500 people. The main industry was agriculture, with any surplus going to urban centres. In the west there were large grain and livestock farms. The steel plough, the mechanical reaper, and improved transportation furthered the commercialisation of agriculture.