The main cause of the collapse of the Aztec Empire was the combination of internal strife and external pressures, particularly the Spanish conquest led by Hernán Cortés. The Aztecs faced dissent from subject tribes who were discontented with their imperial rule, weakening their political cohesion. Additionally, the introduction of European diseases, to which the Aztecs had no immunity, devastated their population. Cortés allied with native groups hostile to the Aztecs, culminating in the siege of Tenochtitlán in 1521. The combination of social unrest, military defeat, and disease ultimately dismantled the empire and marked the beginning of Spanish colonization.