The pope's homily did not directly address Cuba's political situation or its nascent rapprochement with the United States, which he helped broker.
But he warned against personal ambition and an every-man-for-himself mentality, at a time when the communist island faces a delicate period of economic and political transition.
"Christians are constantly called to set aside their own wishes and desires, their pursuit of power, and to look instead to those who are most vulnerable," he told hundreds of thousands of fans and faithful gathered on the iconic square.
"Service is never ideological, for we do not serve ideas, we serve people."
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He paid tribute to Cubans as "a people with a taste for parties, for friendship, for beauty."
"It is a people which has its wounds, like every other people, yet knows how to stand up with open arms, to keep walking in hope," he said.
The mass was the first on the Cuban leg of Francis's most high-profile trip to date, which will next take him to the United States, where he will give landmark addresses to the US Congress and the UN General Assembly.