The pope was welcomed at the airport by Holguin's Bishop Emilio Aranguren and the Cuban government's number two official, Miguel Diaz-Canel, as a large crowd shouted, "Francis our friend, the people are with you!"
Holguin is known for a cross that has overlooked the city from a hilltop since a Franciscan monk hauled it up there in 1790 - though the original wooden version succumbed to old age and the 1950 replacement was destroyed by lightning.
Francis, who began his visit in Havana on Saturday, will celebrate morning mass at a square named for Cuban independence hero Calixto Garcia.
Some 150,000 people are expected.
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"We came to see him because we love him so much for all he has done for peace and for Cuba," said Norales Mendoze, a 45-year-old security guard from the city of Guantanamo who made the nine-hour bus trip to Holguin with hundreds of other faithful.
After mass the pope will visit the hilltop cross to bless the city of 291,000 inhabitants, Cuba's fourth-largest.
According to legend, locals first saw a statue of Cuba's patron saint, Our Lady of Charity of El Cobre, floating in the Holguin bay in 1612 after a storm.
Holguin is the only stop on the pope's eight-day, six-city tour of Cuba and the United States that has never received a papal visit.
After his seven-hour stop in Holguin, the pope takes off for Santiago, the country's second city - dubbed "the heroic city" by the communist regime because Fidel Castro declared there on January 1, 1959 that his revolution had toppled dictator Fulgencio Batista.