He was a successor of Moctezuma and his brothers were Emperors Tizoc and Ahuitzotl and his sister was the Queen Chalchiuhnenetzin. He was an uncle of the Emperor Cuauhtémoc and father of Emperors Moctezuma II and Cuitláhuac.
During his youth, his military prowess gained him the favor influential figures such as Nezahualcoyotl and Tlacaelel I, and thus, upon the death of Moctezuma I in 1469, he was chosen to ascend to the throne, much to the displeasure of his two older brothers, Tizoc and Ahuitzotl.
It is also important that the Great Sun Stone, also known as the Aztec Calendar, was carved under his leadership. In the year 1475 there was a major earthquake that destroyed many homes in Temochtitlán.
Using as a pretext the insulting behavior of a few Tlatelolcan citizens, Axayacatl invaded his neighbor, killed its ruler, Moquihuix, and replaced him with a military governor. The Tlatelolcans lost any voice they had in forming Aztec policy.