Fragile health has prevented the 87-year-old leader of the world's 1.3 billion Catholics from travelling in recent months, his last trip being a visit to the French city of Marseille in September.
But under sunny skies on Sunday, the pope appeared in high spirits as he addressed more than 10,000 faithful seated in the vast St Mark's Square, following an earlier visit to a women's prison and an address to young Venetians.
Citing the "enchanting beauty" of Venice, Francis listed the many dangers facing it -- climate change, mass tourism and "frayed social relations, individualism and loneliness".
"Venice is one with the waters upon which it sits. Without the care and safeguarding of this natural environment, it might even cease to exist," said the pope in his homily.
"Similarly, our life is also immersed forever in the springs of God's love," he said.
Venice, he said, "which has always been a place of encounter and cultural exchange, is called to be a sign of beauty available to all, starting with the last -- a sign of fraternity and care for our common home."
The pope's visit came during the same weekend that Venice launched a new five-euro ($5.35) entry fee for day trippers, aimed at easing the pressure of tourism on the UNESCO World Heritage site.
Francis said one of Venice's main challenges was "the difficulty of creating an environment that is fit for human beings through adequate tourism management" -- along with "climate change... the fragility of constructions, of cultural heritage but also of people".
Tourists were prevented from accessing the square during the papal mass, which required a ticket to attend.
- Suffering and rebirth -
Earlier on Sunday, Francis arrived by helicopter on the island of Giudecca, which houses a women's prison.
Greeting one by one the approximately 80 inmates, the pope encouraged the women to reconstruct their lives "brick upon brick, together, with determination" during their time behind bars.
He urged administrators to offer reintegration programmes.
"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 there," he said, sitting in front of the prisoners.
"But it can also become a place of moral and material rebirth," he added.
The pope also toured the art exhibition housed at the prison.
It considers the daily lives of the inmates through the work of 10 different artists -- the Vatican's entry for this year's Biennale festival of art.
This was the first time a pope had visited the prestigious festival, which began last weekend.
Francis also addressed some 1,500 young people gathered outside the Basilica di Santa Maria della Salute, arriving by speedboat at the landmark church at the entrance to the Grand Canal.
He encouraged them to become engaged in the world despite everyone being "on their own with their cel lphone, glued to social media and video games".
"You must fearlessly go against the current -- take life into your hands, get involved, turn off the TV and open the Gospel, leave the cell phone and encounter people!" he said.
In December, a bout of bronchitis forced the pope to cancel a trip to Dubai, where he was to have addressed United Nations climate talks.
He also pulled out of an Easter event at the last minute in March, after suffering for several weeks from what the Vatican called a "light flu".
- Asia trip -
The visit by Francis, who returned to Rome in the early afternoon, is the fourth papal visit to Venice, after those of Paul VI (1972), Jean-Paul II (1985) and Benedict XVI (2011).
The diocese of Venice is one of the largest in Italy, with 125 parishes, and has close ties with the papacy.
Three Venice patriarchs became pope in the 20th century.
Francis, who uses a wheelchair, has suffered increasing health problems in recent years, from knee pain to surgery to his colon and for a hernia.
Despite the pope's health concerns, the Vatican is planning an ambitious 12-day trip for him to Asia in September, taking in Indonesia, Papua New Guinea, East Timor and Singapore.
Before that, the pontiff is due to visit the Italian cities of Verona and Trieste in May and July respectively.
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