The retirement of Ortega, 79, was long expected because church regulations require bishops to submit their resignation when they reach age 75. But Ortega, like many other bishops, was allowed to serve longer at the pope's discretion.
"I will live more quietly," Ortega told CNN in 2015 on his plans for life after stepping down. "But that doesn't mean that one doesn't still have a sense of social commitment or a presence in the church."
As Havana archbishop for over two decades, Ortega oversaw the visits of three popes to the island and the slow rebuilding of the church, which lost much of its influence after Fidel Castro took power.
Following Castro's 1959 revolution, Ortega, then a young priest, was jailed in a government work camp for suspected opponents.
Decades later, Ortega hand-delivered secret messages from Pope Francis to Barack Obama and Raul Castro that urged the leaders to put aside Cold War-era mistrust and forge a new relationship between the United States and Cuba.
On December 17, 2014, the day Obama and Castro announced the deal that led to prisoner exchanges and negotiations to restore full diplomatic relations, Francis publicly thanked Ortega for his role in the breakthrough.
Ortega greeted Obama at Havana's Cathedral on the first day of the President's visit to Cuba in March. Obama was the first U.S. president to visit Cuba in nearly 90 years.
Often criticized for not openly challenging the government over human rights abuses, Ortega said he found engaging Cuban officials through behind-the-scenes lobbying and diplomacy to be more effective.
"The desire that Raul Castro expressed to the United States: to live together with differences but in a civil way is also what the Cuban Church has expressed to the Cuban government," Ortega told CNN. "The church is not an enemy."
The Vatican statement said Juan de la Caridad García Rodríguez, archbishop of the eastern city of Camagüey, would replace Ortega as archbishop of Havana.
García Rodríguez, 67, is "characterized by his austerity, apostolic devotion, prayer and virtuous living," the statement said.
The statement did not name Ortega's replacement as cardinal of the Cuban church.