The Aztec Empire, home to an estimated 25 million people in the early 1500s, was destroyed by a combination of European diseases, military conquest, and famine. Disease was by far the biggest killer. Epidemics that swept through central Mexico between 1520 and 1580 killed as many as 18 million Indigenous people, dwarfing the death toll from warfare itself.
Smallpox Struck First
In 1520, roughly a year after Spanish forces first arrived in the Aztec capital of Tenochtitlan, a smallpox epidemic broke out. The Aztecs had no prior exposure to the virus and therefore no immunity. The disease spread rapidly through the dense population of the city, killing enormous numbers of people over roughly 60 days.
The epidemic did more than kill civilians. It decimated the Aztec military and leadership at exactly the moment they needed to fight. The Spanish commander Hernán Cortés had been driven out of Tenochtitlan during a fierce Aztec counterattack, but the two months of epidemic gave his forces a critical window to regroup, recruit Indigenous allies, and plan a siege. By the time the Spanish returned, the Aztec army was severely weakened.
The 93-Day Siege of Tenochtitlan
In May 1521, Cortés and a coalition army of Spanish soldiers and tens of thousands of Indigenous allies from rival groups surrounded Tenochtitlan. The siege lasted 93 days. Cortés loaded ships with cannons to control the lake surrounding the island city, and systematically cut off the Aztecs’ food and water supply, including the aqueduct from Chapultepec that provided fresh drinking water.
The result was a slow, grinding catastrophe. Starvation and thirst killed Aztec defenders alongside the ongoing effects of smallpox. Over nearly three months, the Spanish and their allies mounted repeated assaults, gradually pushing into the city. By August 1521, Tenochtitlan fell. But the siege itself was only one chapter. The truly devastating losses came from what followed.
The Cocoliztli Epidemics
Two massive outbreaks of a mysterious illness called “cocoliztli” (a Nahuatl word roughly meaning “pestilence”) struck the surviving Indigenous population in 1545 and again in 1576. These epidemics were far deadlier than smallpox had been. The 1545 outbreak alone killed an estimated 45% of the entire remaining native population of what the Spanish called New Spain.
The symptoms were horrifying. Victims turned yellow from jaundice. Blood ran from their ears and noses. They suffered hallucinations and agonizing convulsions, and many died within days. Historical records from the period describe something resembling a hemorrhagic fever like Ebola. A Spanish account from the 1576 outbreak noted that “the place we know as New Spain was left almost empty.”
For over a century, researchers debated what actually caused cocoliztli. In 2017, a team of scientists extracted ancient DNA from the teeth of 24 skeletons buried in an epidemic cemetery in Oaxaca, southern Mexico, dating to the 1545 outbreak. Using a specialized tool for analyzing ancient pathogen DNA, they identified a strain of Salmonella bacteria, specifically a type that causes enteric fever. This was a common microbe, likely brought by European colonizers or their livestock, but it proved catastrophic in a population already weakened by decades of war, displacement, and prior epidemics. While salmonella today is associated with food poisoning, advanced bacterial infections can cause bleeding from body openings and symptoms that closely mimic hemorrhagic fever, which would explain the terrifying accounts from the time.
Why Disease Was So Devastating
The scale of death from European pathogens is difficult to overstate. The Aztec population had been geographically isolated from the diseases that circulated in Europe, Asia, and Africa for thousands of years. Smallpox, measles, typhus, and enteric fevers were all entirely new to their immune systems. When one epidemic subsided, another arrived, hitting survivors who were already malnourished and displaced from their communities.
The epidemics also arrived in waves that compounded each other’s effects. Smallpox weakened the empire’s ability to resist military conquest. The conquest itself destroyed food systems and social structures. Then cocoliztli struck populations that were already under colonial control, unable to maintain the agricultural and sanitation systems that had previously supported millions. Each crisis made the next one worse.
Spiritual and Social Collapse
The epidemics didn’t just kill people. They shattered the belief systems that held Aztec society together. As disease swept through communities with no apparent cure or explanation, many Aztecs began to blame their own gods for abandoning them. The emperor Montezuma himself reportedly lamented the gods’ failure, and this despair spread widely. Communities that had been loyal to the Aztec Empire lost faith in its spiritual authority.
This crisis of belief had practical consequences. Groups that had long resented Aztec rule saw an opportunity and allied with the Spanish. The empire’s social cohesion dissolved from within even as it faced military pressure from outside. Spanish missionaries pointed to the epidemics as evidence of their own god’s power, accelerating cultural and religious conversion among survivors.
The Scale of Population Loss
From a population of roughly 25 million before Spanish contact, the Indigenous population of central Mexico plummeted over the following decades. Successive waves of smallpox, cocoliztli, measles, and other diseases reduced the population by millions with each outbreak. By the late 1500s, after the second cocoliztli epidemic, the region had lost the vast majority of its pre-contact population. Some estimates suggest that by 1600, fewer than 2 million Indigenous people remained in what had been the Aztec Empire, a decline of over 90%.
Warfare and the siege of Tenochtitlan killed thousands, but disease killed millions. The Aztec Empire fell to Spanish swords in 1521, but the Aztec people continued dying from wave after wave of epidemic for the rest of the century. It was one of the largest demographic catastrophes in recorded human history.