The Spanish conquest of the Aztec Empire was a pivotal event in the history of the Americas, marked by the collision of the Aztec Triple Alliance and the Spanish Empire and its Indigenous allies. Taking place between 1519 and 1521, this event saw the Spanish conquistador Hernán Cortés, and his small army of European soldiers and numerous indigenous allies, overthrowing one of the most powerful empires in Mesoamerica.

Led by the Aztec ruler Moctezuma II, the Aztec Empire had established dominance over central Mexico through military conquest and intricate alliances. Because the Aztec Empire ruled via hegemonic control by maintaining local leadership and relying on the psychological perception of Aztec power — backed by military force — the Aztecs normally kept subordinate rulers compliant. This was an inherently unstable system of governance, as this situation could change with any alteration in the status quo. A combination of factors including superior weaponry, strategic alliances with oppressed or otherwise dissatisfied or opportunistic indigenous groups, and the impact of European diseases contributed to the downfall of the short rule of the Aztec civilization. In 1520, the first wave of smallpox killed 5–8 million people.

The invasion of Tenochtitlán, the capital of the Aztec Empire, marked the beginning of Spanish dominance in the region and the establishment of New Spain. This conquest had profound consequences, as it led to the cultural assimilation of the Spanish culture, while also paving the way for the emergence of a new social hierarchy dominated by Spanish conquerors and their descendants.

Following an earlier expedition to Yucatán led by Juan de Grijalva in 1518, Spanish conquistador Hernándo Cortés led an expedition (entrada) to Mexico. The next year, Cortés and his retinue set sail for Mexico. The Spanish campaign against the Aztec Empire had its final victory on 13 August 1521, when a coalition army of Spanish forces and native Tlaxcalan warriors led by Cortés and Xicotencatl the Younger captured the emperor Cuauhtémoc and Tenochtitlan, the capital of the Aztec Empire. The fall of Tenochtitlan marks the beginning of Spanish rule in central Mexico, and they established their capital of Mexico City on the ruins of Tenochtitlan.

Cortés made alliances with tributary city-states (altepetl) of the Aztec Empire as well as their political rivals, particularly the Tlaxcaltecs and Tetzcocans, a former partner in the Aztec Triple Alliance. Other city-states also joined, including Cempoala and Huejotzingo and polities bordering Lake Texcoco, the inland lake system of the Valley of Mexico. Particularly important to the Spanish success was a multilingual (Nahuatl, a Maya dialect, and Spanish) Nahua-speaking woman enslaved by the Mayas, known to the Spanish conquistadors as Doña Marina, and later as La Malinche. After eight months of battles and negotiations, which overcame the diplomatic resistance of the Aztec Emperor Moctezuma II to his visit, Cortés arrived in Tenochtitlan on 8 November 1519, where he took up residence with fellow Spaniards and their indigenous allies. When news reached Cortés of the death of several of his men during the Aztec attack on the Totonacs in Veracruz, Cortés claims that he took Motecuhzoma captive. Capturing the cacique or indigenous ruler was a standard operating procedure for Spaniards in their expansion in the Caribbean, so capturing Motecuhzoma had considerable precedent but modern scholars are skeptical that Cortés and his countrymen took Motecuhzoma captive at this time. They had great incentive to claim they did, owing to the laws of Spain at this time, but critical analysis of their personal writings suggest Motecuhzoma was not taken captive until a much later date.

When Cortés left Tenochtitlan to return to the coast and deal with the threat of the expedition of Pánfilo de Narváez, Cortés left Pedro de Alvarado in charge of Tenochtitlan. Cortés left with a small army to the coast with the plan of attacking during the night. After defeating Narváez's fleet, Cortés convinced most of his enemy's crew to go with him by promising great riches. Upon reaching Tenochtitlan, Cortés and the new enlarged force received the message that "the Aztec had risen against the Spanish garrison" during a religious celebration. Alvarado ordered his army to attack the unarmed crowd; he later claims that the Aztecs had used the celebration to cover up a counterattack. Cortés realized that the defeat was imminent and decided to escape; yet, the Aztecs attacked. The Massacre is most known as La Noche Triste (the sorrowful night), where about "400 Spaniards, 4000 native allies and many horses [were killed] before reaching the mainland". Moctezuma was killed, although the sources do not agree on who killed him. According to one account, when Moctezuma, now seen by the population as a mere puppet of the invading Spaniards, attempted to calm the outraged populace, he was killed by a projectile. According to an indigenous account, the Spanish killed Moctezuma.

The Spanish, Tlaxcalans and reinforcements returned a year later on 13 August 1521 to a civilization that had been weakened by famine and smallpox. This made it easier to conquer the remaining Aztecs. The Spaniards' victory is attributed to their help from indigenous allies, technology, and the Aztec empire's vulnerability due to the smallpox spread. As a result, the Aztec's tactics countering the Spaniard's advanced technology is understated. According to Hassig, "It is true that cannons, guns, crossbows, steel blades, horses and war dogs were advanced on the Aztecs' weaponry. But the advantage these gave a few hundred Spanish soldiers was not overwhelming." In the words of Restall, "Spanish weapons were useful for breaking the offensive lines of waves of indigenous warriors, but this was no formula for conquest ... rather, it was a formula for survival, until Spanish and indigenous reinforcements arrived."

The integration of the indigenous allies, essentially, those from Tlaxcala and Texcoco, into the Spanish army played a crucial role in the conquest, yet other factors paved the path for the Spaniards' success. These alliances not only expanded the Spanish ranks, but also provided essential guidance on local geography and effective tactics against Aztec defenses. For instance, the Spaniards' timing of entry, the compelling ideologies of both groups, and the Spanish unfamiliarity with the Aztec Empire. Therefore, the Spaniards lacked a sense of danger and power structure within the empire. "A direct attack on a city as mighty as Tenochtitlan was unlikely and unexpected" from the enemy empires. As well, it was very uncommon that an attacking army would come unannounced. In addition, aside from the infantry and the allies' role in the Spanish conquest, cavalry was the "arm of decision in the conquest" and "the key ingredient in the Spanish forces". Many of those on the Cortés expedition of 1519 had never seen combat before, including Cortés. A whole generation of Spaniards later participated in expeditions in the Caribbean and Tierra Firme (Central America), learning strategy and tactics of successful enterprises. The Spanish conquest of Mexico had antecedents with established practices.