It was the 87-year-old Pope's first visit to the lagoon city since his 2013 election and the first time a pontiff has been to the Venice Biennale - a prestigious art show with exhibitions sponsored by numerous nations in myriad spaces.
The Vatican's exhibition has been set up in a women's prison and the Pope opened his trip by flying directly into the Giudecca jail by helicopter to view the show entitled Through My Eyes.
"Prison is a harsh reality, and problems such as overcrowding, the lack of facilities and resources, and episodes of violence, give rise to a great deal of suffering," he said.
"But it can also become a place of moral and material rebirth.
"Let us not forget that we all have mistakes to be forgiven and wounds to heal," he told a group of inmates and guards seated in the courtyard of the prison.
The Pope will attend mass at St Mark's Basilica in Venice, with thousands expected to attend. (AP PHOTO)
The unusual decision to house the Holy See pavilion in the jail highlights the Pope's repeated calls for society to rally around the poor and neglected, including prison populations.
The Vatican exhibit features creations by nine contemporary artists who worked closely with inmates on the project.
It is the Pope's first trip beyond Rome since a brief visit to France in September.
He had been due to attend a climate change conference in the United Arab Emirates in December but pulled out shortly beforehand after coming down with the flu.
Francis uses a cane or a wheelchair to move around due to a knee ailment and suffers from repeated bouts of bronchitis and flu.
He unexpectedly withdrew from a Good Friday procession in March "to preserve his health", but has looked well since then.
After leaving the jail, the Pope was due to travel by motorboat to the 16th century church of La Madeleine to talk to young Venetians before attending mass at St Mark's Basilica.
About 10,000 people are expected to attend the service, with thousands more likely to fill the giant St Mark's Square outside to follow it on large screens.
The Venice trip is the first of four planned inside Italy in the next three months.
Francis is scheduled to visit Verona in May and Trieste in July and is expected to attend a June summit of Group of Seven (G7) leaders in Bari.
In September, he is set to embark on the longest foreign trip of his papacy, travelling to Indonesia, Papua New Guinea, Timor-Leste and Singapore from September 2-13.
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