Although a variety of infectious diseases existed in the Americas in pre-Columbian times, the limited size of the populations, smaller number of domesticated animals with zoonotic diseases, and limited interactions between those populations (as compared to areas of Eurasia and Africa) hampered the transmission of communicable diseases.

The Cocoliztli Epidemic or the Great Pestilence was an outbreak of a mysterious illness characterized by high fevers and bleeding which caused 5–15 million deaths in New Spain during the 16th century.

Diseases and epidemics of the 19th century included long-standing epidemic threats such as smallpox, typhus, yellow fever, and scarlet fever.