The Mass was celebrated at Cuba’s holiest shrine, the sanctuary of the Virgin of Charity of El Cobre.
Pope Francis then left for the United States, where he will address both houses of Congress.
The Pope has avoided any overt political statements during his visit to Cuba.
Commentators say the pontiff is expected to be more outspoken while in the US.
In Washington DC he will hold the first-ever canonization mass on US soil and then give the first address to Congress by a pope.
Pope Francis will then head to New York City for the 70th anniversary of the United Nations General Assembly.
The final leg of Pope Francis’ US tour is Philadelphia where the pontiff will preside over the Vatican’s World Meeting of Families.
It is being billed as one of the largest events in Philadelphia in modern times and could attract up to a million and half people.
During his time in Cuba, Pope Francis asked Cubans to follow the example set by the Virgin of Charity of El Cobre “to build bridges, to break down walls, to sow seeds of reconciliation”.
The Virgin symbolizes Cuba’s mixed Spanish and African roots.
Alluding to Cuba’s 1959 Communist revolution which brought Fidel Castro to power, Pope Francis said: “Our revolution comes about through tenderness, through the joy which always becomes closeness and compassion, which isn’t pain, and leads us to get involved in, and to serve, the life of others.”
During the trip, there have been complaints from some Cuban dissidents that Pope Francis did not receive them to hear their concerns about human rights on the island.
The Vatican said such a meeting was never on the agenda.
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