President Obrador wants Spain to apologise for the conquest that caused the near-extermination of its indigenous peoples but Spain has refused.
A near life-size replica of the Aztecs' twin temples has been lit up in an anniversary ceremony in Mexico City's main plaza.
Exactly five centuries ago on Friday the city was seized by the Spanish and the Aztec Empire was defeated.
Noticeably absent from the ceremony was Spain's ambassador, who wasn't invited.
President Obrador wants Spain to apologise for the conquest of Mexico which caused the near-extermination of its indigenous peoples, but it has refused.
"This disaster, cataclysm, catastrophe, whatever you want to call it, enables us to say that the conquest was a resounding failure," he said in his address.
The ceremony was attended by indigenous representatives from Mexico, Canada, and the United States as well as descendants of the late emperor Moctezuma II.
"What civilization can we talk about if the lives of millions of human beings are lost and the nation, the empire or the dominant monarchy does not manage in three centuries of colonization to recover the population that existed before the military occupation?" he said.
Standing in the Zocalo square, once the heart of the Aztec empire, Lopez Obrador recounted the diseases brought by the conquistadors, and accused them of plundering large amounts of gold.
Conquest and colonization "are signs of backwardness, not of civilization," said the leftist leader, who has previously called on Spain and the Catholic Church to apologise.