Black Death, 1346-1353
Number dead: Anywhere between 30% and 70% of the population
Before you criticize that huge range of death estimates, keep in mind that all the bookkeepers were DYING OF THE PLAGUE. The Black Death -- caused by Yersinia pestis bacteria -- actually triggered a few centuries of flare-ups across the continent. The first wave, though, was the most terrifying, spreading to nearly every corner of Europe, killing tens of millions, and forcing you to read The Decameron.
Cocoliztli, 1545-1548; 1576
Number dead: 7-17 million
As though Europeans didn’t do enough to destroy indigenous populations in the Americas, a viral hemorrhagic fever called “cocoliztli” (the Nahuatl word for “pestilence”) absolutely ripped through the Mexican population twice. The first time, from 1545 to 1548, it killed between 5 and 15 million people, which accounted for about 80% of the total native population; cocoliztli’s return 30 years later was tame by comparison, killing 2 to 2.5 million, or about 50% of those who remained.