The most significant factor was the spread of Eurasian infectious diseases, such as smallpox and measles, to which the Aztecs had no immunity. These diseases caused widespread death and weakened the Aztec empire, making it more vulnerable to attack.
Warfare
The Spanish conquistadors, led by Hernan Cortes, arrived in Mexico in 1519 and quickly formed alliances with the Aztec's enemies. In a decisive battle in 1521, the Spanish and their allies defeated the Aztec army and captured the Aztec capital, Tenochtitlan.
Political instability
The Aztec empire was also facing internal problems, including a civil war and a succession crisis. This weakened the empire and made it more difficult for the Aztecs to resist the Spanish invasion.
Religion
The Aztec religion, which involved human sacrifice, was also a factor in the empire's downfall. The Spanish were horrified by these practices and used them as justification for their conquest.