His tightly packed schedule in one of the poorest regions of Italy will see the pontiff visit a prison, hospital and care home in and around Cassano allo Jonio before celebrating mass with an expected 100,000 pilgrims.
The pope will likely speak out about two of the region's biggest challenges: towering youth unemployment and the pervasive grip of the powerful and secretive 'Ndrangheta crime group.
Unemployment among the under-25s in the region stands at 56.1 percent – the highest in Italy in 2013 according to Eurostat — and local mobsters thrive by offering idle youngsters work, luring them into their networks.
The Argentine pope has denounced the mafia, warning mobsters to relinquish their "bloodstained money" which "cannot be taken to heaven".
After meeting relatives of mafia victims in May – including the families of butchered children and priests – he told gangsters that they would "go to hell" if they did not repent.
When John Paul II voiced a similar threat in Sicily in 1993 the Cosa Nostra mafia responded by bombing two historic churches in Rome.
Francis's determination to rattle organised crime groups has sparked warnings that he himself could become a target, with respected Calabrian state prosecutor Nicola Gratteri saying in November that the 'Ndrangheta was "nervous".
"If the mafia bosses can trip him up, they won't hesitate," he said. The Vatican brushed off the warning, insisting there was "no reason for concern".
The town of Cassano allo Jonio, nestled at the bottom of a steep mountain, was home to Nicola "Coco" Campolongo, a three-year-old shot dead in January along with his grandfather in an apparent mob hit over money.
The discovery of their bodies in a burnt-out Fiat Punto sent shockwaves through Italy, as did the murder just two months later of another three-year-old in the nearby Puglia region.
Code of loyalty
During his visit to Castrovillari prison, the 77-year-old pope will meet Coco's father, who was serving time alongside the toddler's mother for drug crimes when their son was killed.
He may also meet the man who murdered priest Lazzaro Longobardi, who was beaten to death with an iron bar the same month after a failed extortion attempt.
The 'Ndrangheta plays a leading role in the global cocaine trade and its bastion, the Calabria region, is a major transit point for drug shipments from Latin America to the rest of Europe.
It has benefitted in the past from historic ties to the Church, with dons claiming to be God-fearing Catholics and priests turning a blind eye to crimes.
But over the past 20 years numerous priests have taken part in the fight against the clans – sometimes paying for their bravery with their lives.
Francis is likely to call on anti-mafia campaigners to continue their struggle, praising the work of organisations like Progetto Sud in Lamezia, which has transformed a gambling arcade and drug-trafficking base into a community for handicapped people.
He may also hail the courage of those who break ranks with the mob despite the clans' stringent code of loyalty, which punishes rebellion by death.
The 'Ndrangheta has been successful in combining elements of archaic tradition with modernity and has proved particularly difficult to infiltrate because of its reliance on a tightly knit network of families.
But a small but growing number of wives and daughters in particular are speaking out against their mobster fathers, brothers or sons.