Lampedusa island has seen tens of thousands of arrivals since the start of the Arab Spring revolts in 2011, many of them leaving behind African homelands and taking to overcrowded fishing trawlers and rubber dinghies.
Hundreds have drowned in the process and the head of the Roman Catholic Church will honour them by casting a wreath into the sea in their memory, before taking a boat to the same pier where many of the migrants first set foot on dry land again.
A group of recent arrivals will meet the pope there.
"The pope is going there to cry for the dead," his secretary, Alfred Xuereb, told reporters this week.
"His presence is a signal that in the North there are rich people who waste, while in the South there are those who leave everything behind," he said.
The Catholic Church has often been a strong advocate for migrants and has called for their rights to be better protected by host countries, as well as providing food aid and shelter through its charities.
The pope has said he does not want to be accompanied by any politicians, with the Vatican turning down a request from Interior Minister Angelino Alfano, on what will be his first visit outside Rome since his election in March.
Francis is also expected to pay homage to the local population of 6,000 souls, a quiet fishing community that has been overwhelmed by the arrivals but has shown a constant readiness to help those in need.
The pope will be given a small crucifix made by a local artist with wood from the boats on which the migrants arrive, which lie abandoned on the island.
"Christ is on the island in those who arrive but also in the local population that welcomes them," Cardinal Antonio Maria Veglio, head of the Pontifical Council for Migrants, wrote in the Vatican's official daily.
The tiny island of Lampedusa, measuring 20 square kilometres (7.8 square miles), is a popular summer destination and once housed a US Coast Guard base during the Cold War now used to house migrants.
The rocky outcrop is closer to North Africa than to the Italian mainland and is on the same latitude as central Tunisia, a proximity that has meant historical ties going back centuries and cooperation in fishing.
The migrant centre on the island is often criticised by campaigners for being overcrowded and unsanitary, while many unaccompanied minors are stuck on the island for months as they await suitable housing.
Within days of their arrival, adults are transferred from Lampedusa to migrant detention centres on the mainland to be deported or to refugee centres if they file asylum claims in line with Italian laws.
The pope's visit will send "a strong signal" to governments about immigration, Veglio said.
The cardinal said the places where migrants and refugees are held and the way they are treated "should be questioned" and called for full rights on "freedom of movement and freedom to work" in host countries.
Italian parliament speaker Laura Boldrini, a former United Nations official working on refugee issues in Rome who has visited Lampedusa many times during her career, said the visit was "historic".
"It is a warning against the ideological campaigns that degrade social cohesion by denouncing an non-existent invasion and spread fear," she said.
Boldrini said that while Italy's asylum system was working well, the "real problem" was integration. She said the lack of assistance for new arrivals meant they were "condemned to live on the fringes".
Lampedusa has also been a magnet for politicians who oppose immigration, like French National Front leader Marine Le Pen who visited in 2011 warning of an imminent "catastrophe" caused by the boat people.
There has been an increase in arrivals on Lampedusa in recent weeks because of improved weather conditions, with more than 3,600 arriving so far -- three
times more than during the same period last year.
But the numbers are still far from the peaks reached in 2011 when tens of thousands arrived within months as border controls in Libya and Tunisia disappeared during Arab Spring revolts.