But the trip, the 22nd foreign trip during his tenure, could be overshadowed by security concerns, protests and church-related scandals.
The six-day trip will take Pope Francis, who is 81 years old, across Chile and Peru, to celebrate Mass and deliver speeches. The Argentine Pope has visited both countries before becoming pope and lived in Chile for over a year while studying with the Jesuit order to become a priest.
As is his custom, he is expected to focus on the people living on the margins of society, the poor and the sick, including meeting female convicts and their children at a Santiago prison. He also has a scheduled lunch with eight of the Mapucho people in Chile who have grievances with the Catholic church.
And massive crowds are expected at nearly every place Pope Francis will visit, and to line the streets to see his Pope-mobile.
At least three homemade bombs went off in churches in Santiago last week, causing minor damage yet no injuries. Threats to Pope Francis were found in notes. And protests are expected there over a bishop whom Pope Francis appointed in 2015.
The bishop, who was appointed to a town near Santiago, is accused of covering up sexual abuse by a priest in the 1980ss and 1990s. Some parishioners in the town say they were denied requests to meet with the pope during his trip and are now planning to protest during his stay.
Vatican spokesman Greg Burke told journalists at a briefing Thursday there's a chance Pope Francis would meet with victims of clerical sex abuse privately in Chile, describing it as "not impossible." The meeting had not been set up, though.
Tens of thousands of people were killed, tortured or imprisoned for political reasons in Chile during Pinochet’s reign and many others went into exile.
Sex abuse cases have hurt the church's reputation in Peru, too. Last week, the Vatican announced it had taken over a Peru-based Catholic movement, Sodalitium Christianae Vitae, whose founder was accused of sexual and psychological abuse. The conservative movement has about 20,000 members throughout South America and the U.S.
Meanwhile, Pope Francis will not be visiting Argentia, drawing great speculation and questions. Asked why the Pope will be returning to South America for the sixth time but has still not been back as pope to Argentina, Burke cited "personal reasons."
He added, however, that the Pope’s plane will fly over the country, and that the pope is expected to issue a "significant message" to his native land.
Argentina will not be sending any special representative to neighboring Chile for his visit but up to 1 million Argentine pilgrims are expected to cross the border to catch a glimpse of their native son.
This will be the Pope’s first foreign trip in 2018. Future trips have yet to be announced officially, but a visit to Ireland in August is being planned.
Vatican officials are studying the possibility of at least another trip this year, possibly to the Baltics or Asia.