The pontiff compared them to Mary and Joseph, recounting the Biblical story how they had to travel from Nazareth to Bethlehem but found no place to stay.
Many migrants, he said, were being forced to flee from leaders who “see no problem in shedding innocent blood”.
Francis will give his traditional “Urbi et Orbi” Christmas address on Monday.
“So many other footsteps are hidden in the footsteps of Joseph and Mary,” the 81-year-old Argentine pontiff, himself the grandson of Italian migrants, told worshipers in St Peter’s Basilica in the Vatican City on Sunday evening.
“We see the tracks of millions of persons who do not choose to go away but, driven from their land, leave behind their dear ones.”
The leader of the world’s estimated 1.2bn Roman Catholics also stressed that faith demanded that foreigners be welcomed everywhere.
Pope Francis has made defense of migrants around the world a major theme of his papacy.
His comments come as the number of refugees worldwide exceeds 22 million, with the latest cross-border influx being the Rohingya fleeing violence in Myanmar.