Most of depopulation of the Native American population in the 16 century can be attributed to

Diseases, mostly smallpox, that were brought to them during the period of European colonization and conquests.

Explanation:

It is interesting to stress out that although Europeans managed to destroy many Native civilizations through the means of war, many Natives actually died due to diseases. The deadliest among them were the smallpox. Natives didn't had developed immune system to this diseases and literally millions died because of it.

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