The region, mired in poverty and plagued by rising insecurity, has fallen far behind other parts of the country economically.
Preaching to a packed crowd at a sports ground in the southern state of Chiapas, the Pope quoted the Popol Vuh, a sacred Maya text, and drew comparisons between Catholic and Indigenous values.
"Today's world, ravaged as it is by a throwaway culture, needs you!" he said as he celebrated a Mass that included bible readings in native tongues, referring to the mostly Indigenous throngs who loudly cheered him.
"You have much to teach us," he said, lauding Mexico's native peoples while denouncing "the systemic and organised way your people have been misunderstood and excluded from society."
Many women wore Indigenous dress of black skirts and colourful tops, their hair braided with ribbons and parts of the Mass were said in the Tzeltal, Ch'ol and Tzotzil languages.
The state of Chiapas was the scene of the Zapatista uprising of Maya rebels in the 1990s. It is now the frontline of a government crackdown on illegal immigration to the United States from Central America.
In the colonial mountain city of San Cristobal de las Casas, the Pope will visit the church that houses the tomb of Bishop Samuel Ruiz, a champion for Indigenous rights and served as a mediator between the Zapatistas and the government.
Ruiz, who died in 2011, long lobbied to permit mass in languages such as Tzotzil because many of the region's Maya residents do not speak Spanish.
"He is bringing a message for us to ... become Catholic again," said Roco Roman, 58, a local bank manager.
"San Cristobal used to be more Catholic, but many people, mostly Indigenous, have converted to other religions."
The Pope last year apologised for the role of the Church in the conquest of Latin America, and he is expected to formalise a Vatican decree while in Chiapas to authorise translations of the liturgy.