A day after adoring crowds welcomed his arrival, Francis left the Vatican ambassador's residence aboard the popemobile on his way to the National Palace for talks with President Enrique Pena Nieto.
The Catholic faithful again lined the streets of the sprawling capital, cheering as the 79-year-old Argentine-born pontiff waved back at them.
"He's our spiritual guide and we hope that he supports us in this difficult moment for our country," said Magdalena Caballero, a 50-year-old government worker whose nephew was kidnapped a few weeks ago. "His presence fills us with hope."
The choice of location has symbolic significance as none of the pope's predecessors were ever invited at the palace, even though heads of states are usually greeted there.
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While Mexico is the world's second most populous Catholic country after Brazil, governments throughout most of the 20th century were militantly secular and had testy ties with the Church.
But diplomatic relations with the Vatican were restored in 1992.
The pope's presence at the National Palace "closes a cycle," said Mexico's ambassador to the Vatican, Mariano Palacios Alcocer.
The palace meeting "offers a study in contrasts" between a popular pope and "an unpopular head of state who faces one setback after another," said Andrew Chesnut, religion professor at Virginia Commonwealth University.
"It's the Mexican president, of course, who has the most to gain from basking in the glow of one of the world's most popular figures," Chesnut told AFP.
Hours before arriving in Mexico, Pope Francis took care of another, much older rift by holding a historic meeting with the head of the Russian Orthodox Church, Patriarch Kirill, in Cuba in a bid to end a 1,000-year-old Christian rift.