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Spanish conquest
Main article: Spanish conquest of Mexico
The empire reached its height during Ahuitzotl's reign. His successor was Motecuhzoma Xocoyotzin (better known as Moctezuma II), who was Hueyi Tlatoani when the Spaniards arrived in 1519. After a long battle and the siege of the capital, Tenochtitlan, where much of the population died from hunger and smallpox, Cuauhtémoc surrendered to Hernán Cortés, who had an estimated 500 Spanish soldiers and thousands of allies from Tlaxcala and Texcoco, who were resisting Aztec rule. Tenochtitlan's forces were defeated on August 13, 1521.
The fall of Tenochtitlan usually is referred to as the main episode in the process of the conquest of Mesoamerica. Accounts of the Spanish conquest of Mexico often stop with the fall of Tenochtitlan and leave the reader to assume that the rest of the conquest was quick and easy. However, the process of conquering Mesoamerica was much more complex and took longer than the three years that it took Cortés to conquer Tenochtitlan. It took almost 60 years of wars for the Spaniards to conquer Mesoamerica (Chichimeca wars), a process that could have taken longer were it not for three separate epidemics that took a heavy toll on the Native American population. The Spanish conquest of Yucatán took almost 170 years.
Most of the Mesoamerican cultures were intact after the fall of Tenochtitlan. The freedom from Aztec domination may have been considered a positive development by most of the other cultures. The upper classes of the Aztec empire were considered as noblemen. They learned Spanish, and several learned to write in Roman characters. Some of their surviving writings are crucial to our knowledge of the Aztecs. In addition, the first missionaries tried to learn Nahuatl and some, like Bernardino de Sahagún, set out to learn as much as they could of the Aztec culture. All this changed rapidly and eventually, the Indians were forbidden to study by law and had the status of minors.
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Population decline
Main article: Population history of American indigenous peoples
The first epidemic, an outbreak of smallpox (cocoliztli) occurred in 1520 and 1521, decimated the population of Tenochtitlan and was decisive in the fall of the city. Two more epidemics, of smallpox (1545-1548) and typhus (1576-1581) killed up to 75% of the population of Mesoamerica. The Spaniards, trying to make more of the diminishing population, merged the survivors from small towns into the bigger ones. This broke the power of the upper classes and dissolved the coherence of the indigenous society. Collected in larger towns, the people were more susceptible to epidemics due to the higher population density.
The population before the time of the conquest is estimated at 15 million; by 1550, the estimated population was 4 million and by 1581 less than two million. Thus, the "New Spain" of the 17th century was a depopulated country and many Mesoamerican cultures were wiped out. Because of the fall of their social structure, the population had to resort to the Spanish to maintain some order. In order to have an adequate supply of labor, the Spaniards began to import black slaves; most of them eventually merged with the local population.
I wouldn't call 75% kiled by diseases a side-effect or a bonus.