As stated above, Europeans brought with them many diseases to which Native Americans had no immunity, with devastating effects on Native communities. According to Charles C. Mann in the 2005 book 1491, the Native American population in North and South America was much larger than has been previously estimated, and diseases wiped out much more of the population than perviously thought.

Cultural misunderstandings about land ownership and what that meant caused conflicts between Native groups and European settlers. Already reduced Native populations were often forced off their land, disrupting cultures and religions that were tied closely to a particular geography.

As the European culture of the United States gradually grew and pushed westward across the continent, Native Americans increasingly had to cope with being treated as an inferior group that was treated according to what was convenient for white society.

The effects of European "discovery" of the Americas on the people who already lived there were dramatic. First, and most obvious, the introduction of European diseases (for which native peoples had no immunity) led to massive epidemics that ravaged Indian peoples across both North and South America. Smallpox, typhus, malaria, measles, and plague carried off millions of Native Americans in the wake of European contact and exploration. This was the reality faced by most Indian peoples, and it was, in many places, followed shortly thereafter by conquest. But in most of North America in particular, the process was more complex. Natives were not simply pushed aside in places like the Great Lakes, the Southeast, or the Southwest. Rather, Indian people traded, formed alliances, and made war on Europeans, all in an attempt to manage the presence of the invaders to their benefit. In almost all cases, this process ended in the taking of Indian lands, but this sometimes took a very long time. In the short term, Indian peoples married whites, they used (often repurposed) European trade goods, they converted (often on their own terms) to Christianity, and they generally tried to make the best of what we can now see was a dire situation.