Pope Francis asked Mexico's indigenous population for forgiveness over the exclusion they have suffered as he led a mass in native languages in the state of Chiapas.
The Pope also used the open-air service in San Cristobal de las Casas to warn that the world faces "one of the greatest environmental crises" in its history.
"The environmental challenge that we are experiencing and its human causes, affects us all and demands our response," the 79-year-old pontiff said.
"We can no longer remain silent before one of the greatest environmental crises in world history," he told the indigenous crowd.
"In this regard, you have much to teach us. Your peoples...know how to interact harmoniously with nature," he added.
"And yet, on many occasions, in a systematic and organised way, your people have been misunderstood and excluded from society," he said.
"How sad this is. How worthwhile it would be for each of us to examine our conscience and learn to say, 'forgive me.' Today's world, ravaged as it is by a throwaway culture, needs you."
Pope Francis' visit to the largely indigenous and least Catholic state in Mexico comes in the middle of a five-day trip that he has already used to speak out against crime and corruption.
Today, he will speak to youths in Morelia, the capital of Michoacan state, where warring drug gangs cook much of the methamphetamine smuggled into the US.
He will then travel to Ciudad Juarez, which borders the US state of Texas, where he will pray for migrants and victims of violence.