The empire reached its height during Ahuitzotl's reign, 1486 until 1502. His successor, Motecuzōma Xocoyotzin (better known as Montezuma or Moctezuma II), had been Hueyi Tlatoani for 17 years when Hernán Cortés and the Spaniards landed on the Gulf Coast in the spring of 1519.

Despite some early battles between the two, Cortés allied himself with the Aztecs’ long-time enemy, the Confederacy of Tlaxcala, and arrived at the gates of Tenochtitlan on November 8, 1519.

The Spaniards and their Tlaxcallan allies became increasingly dangerous and unwelcome guests in the capital city. In June, 1520, hostilities broke out, culminating in the massacre in the Main Temple and the death of Montezuma. The Spaniards fled the town on July 1, an episode later characterized as La Noche Triste (the Sad Night). They and their native allies returned in the spring of 1521 to lay siege to Tenochtitlan, a battle that ended that August 13 with the destruction of the city. During this period the now crumbling empire went through a rapid line of ruler succession. After the death of Moctezuma II, the empire fell into the hands of severely weakened emperors, such as Cuitláhuac, before eventually being ruled by puppet rulers, such as Andrés de Tapia Motelchiuh, installed by the Spanish.

Despite the decline of the Aztec empire, most of the Mesoamerican cultures were intact after the fall of Tenochtitlan. Indeed, 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 noblemen by the Spaniards and generally treated as such initially. All this changed rapidly and the native population were soon forbidden to study by law, and had the status of minors[citation needed].