The Argentinian pontiff is due to spend around two hours in private conversation with Russian Orthodox Patriarch Kirill at Havana's Jose Marti airport.
It will be the first meeting between the leaders of Christianity's two biggest churches since a 1054 schism that helped to shape modern Europe and the Middle East.
Francis and Kirill are due to sign a joint declaration on the contemporary persecution of Christians in places such as Iraq and Syria.
The rapprochement with the Orthodox wing of Christianity is in line with Francis's drive to make the Vatican a more active player in international diplomacy.
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"I just wanted to embrace my Orthodox brothers," he said in an interview this week. But he also framed the encounter in a broader context of engaging Russia, saying Moscow could be an important partner for peace in the world.
"In the background there is a third player (Putin)," Vatican expert Marco Politi wrote in a blog on the historic encounter.
"It would be naive to believe the sudden availability of the Patriarch is unrelated to the geopolitical situation Russia finds itself in at the moment," he argued, in a reference to Russia's intervention in Syria.
A spokesman for the Orthodox church in Moscow said he could "100 per cent guarantee" that there was no political agenda behind the two religious leaders' meeting.
Despite the breakthrough of a face-to-face meeting, Vatican-Orthodox relations remain strained.
The issues that caused the schism in the first place are unresolved and there are tensions over the perceived evangelism of the Catholic Church in Eastern Europe. Then there is the fallout from the conflict in Ukraine, which has pitted Ukrainian Catholics loyal to Rome against separatists who are mostly Russian Orthodox.