Visiting 14 years after Pope John Paul II's landmark trip to Cuba, and arriving after a stop in Mexico, Benedict will pay homage to the island's patron saint, a diminutive doll-like figurine known as the Virgin of Charity of El Cobre, and say Masses in the eastern city of Santiago de Cuba and in Havana.
He comes to Cuba at a time when Church-state relations have warmed after decades of hostility that followed the island's 1959 revolution.
But the pontiff fired an unexpected salvo on Friday when he told reporters that communism on the Caribbean island had failed and a new economic model was needed, adding that the Church was willing to offer its help "to avoid traumas."
The Cuban government offered a diplomatic response to the Pope's criticism, saying that Cuba would "listen with all respect" to the Pope and welcomed "the exchange of ideas."
While many Cubans complain about the failings of the socialist economy, not everyone agrees with the Pope's assessment.
"We're so happy the Pope is coming, it makes us feel as though the world is noticing us," said Alejandro Linares, a 23-year-old university student from the eastern province of Guantanamo, a small image of revolutionary icon Ernesto 'Che' Guevara dangling around his neck.
"We want him to see our Cuba. We want him to see that we live pretty well here and that we want to be socialist, not capitalist."
President Raul Castro has used the Church as an interlocutor on issues such as political prisoners and dissidents, while moving forward on reforms to Cuba's rickety Soviet-style economy. They include slashing a million government jobs and freeing up some sectors to small-scale private enterprise.
Though weakened after more than half a century of communist rule, the Church remains the largest and most socially influential institution outside of the government in Cuba.
Since the visit by Pope John Paul, the Church has sought to increase its social outreach, offering care centers for the elderly as well as limited after-school and adult education programs, though it is denied permission to compete with Cuba's state-run school system.
Raul Castro will meet Benedict at the airport in Santiago de Cuba, which is Cuba's second biggest city at the eastern end of the island, and then hold official talks with him on Tuesday in Havana.
It was not yet known if Benedict, 84, would meet former Cuban leader Fidel Castro, who is 85 and Raul's older brother, or Venezuelan President Hugo Chavez, 57, who arrived in the Cuban capital over the weekend for cancer treatment.
Chavez has become more publicly religious since he was operated on for cancer last summer in Cuba. Unconfirmed reports out of Venezuela said the pope would see him in Havana.
During his visit to Mexico, Benedict denounced drug violence and corruption. In Cuba, he is expected to push for a bigger role for the Church.
Many Cubans would like the pope's visit to help bring an end to the 50-year-old trade embargo the United States has imposed on the island.
"All Cubans would like the pope's visit to have repercussions that help end the embargo, but we don't need a new system," said Sergio Teyes, 40, sitting next to the frayed 1950 Chevrolet Deluxe classic car he uses to drive tourists around town, its bumpers and trim dented and blue paint flaking off.
"The economy has been improving, growing. Education and healthcare is paid for," he added. "Marxism will always be the idea, but with improvements. One thing we could do with are better salaries."
Close to the pergola where the pope will say Mass in Santiago de Cuba's main square, a placard pictures a young Fidel in fatigues thrusting a rifle into the air.
The Communist Party ended its ban on religious believers in 1991, but Cubans generally view John Paul's visit as the pivotal moment that led to improved Church-state relations.