It is hard to determine the actual number of Native Americans killed during this period. Diseases ravaged entire tribes through contact with European explorers and trade. Smallpox had arrived on the Western plains long before the first American settlers ever made contact with the Lakota nation. Squanto, the famous Native American who befriended the Pilgrims, lost his entire tribe to disease. Entire Eastern tribes succumbed to disease and starvation.

Many more lost their lives as slaves, though Europeans would soon prefer to use Africans, as they survived better and more easily took on European-style agricultural techniques. North America lost entire tribes, along with their languages and cultures.

While it is easier to count Native American deaths from battles, it was disease that killed the majority of them. Life on reservations was hard as well, indirectly causing the death of many Native Americans and lowering the overall life expectancy on the reservations. Currently, reservations are still some of the poorest areas of the United States.