The pontiff celebrated Mexico's Indians during a visit to the southern state of Chiapas.
He presided over a Mass in three native languages thanks to a new Vatican decree approving their use in liturgy.
The first Latin American pope spoke of his two main concerns in the region; the importance of looking after the environment as well as appreciation for indigenous cultures of the Americas.
Earlier in the week he issued an apology for the Catholic Church's colonial-era crimes against indigenous people in the Americas.
Among the poor being treated worst is our planet. We cannot pretend all is fine in the face of the great environmental crisis.
— Pope Francis (@Pontifex) February 15, 2016
In the mountain city of San Cristobal de las Casas, he said: "The environmental challenge that we are experiencing and its human causes affects us all and demands our response.
"We can no longer remain silent before one of the greatest environmental crises in world history."
He commented: "In this regard, you have much to teach us."
As the pontiff arrived crowds chanted "Francis friend, San Cristobal is with you."
Around half a million Catholics gathered to see the pope in the city and around 100,000 gathered in a field for a special Mass.
The leader of the Catholic Church also spoke about boosting the faith in the least Catholic state in Mexico.
The Mass featured readings, prayers and hymns in the three main indigenous languages of Chiapas: Tzeltal, Tzotzil and Chol, which are spoken by just over one million people, according to Mexico's latest census.
Pope Francis will next leave for Morelia to hold a Holy Mass and then on to Ciudad Juárez before he departs back to Rome.