Pope Leo XIV is demanding that Israel cease the "collective punishment" and forced displacement of Palestinians in Gaza, pleading for an immediate and permanent ceasefire in the besieged territory.
His impassioned appeal comes amid preparations by Israel for a new military offensive.
During his weekly general audience on Wednesday, attended by thousands in the Vatican’s auditorium, Leo was interrupted twice by applause as he read aloud his latest call for an end to the 22-month war.
He also urged the release of hostages taken by Hamas in southern Israel, 50 of whom remain in Gaza.
He further called for both sides and international powers to end the conflict, which he said "has caused so much terror, destruction and death".
“I beg for a permanent ceasefire to be reached, the safe entry of humanitarian aid to be facilitated and humanitarian law to be fully respected,” Leo said.
He cited international law requiring the obligation to protect civilians and “the prohibition of collective punishment, indiscriminate use of force and the forced displacement of the population”.
Palestinians in Gaza are bracing for an expanded offensive promised by Israel in some of the territory's most populated areas including Gaza City, where famine has been documented and declared.
Israeli Prime Minister Benjamin Netanyahu has said Israel will launch its Gaza City offensive while simultaneously pursuing a ceasefire, though Israel has yet to send a negotiating team to discuss a proposal on the table.
He has said the offensive is the best way to weaken Hamas and return hostages, but hostages' families and their supporters have pushed back, saying it will further endanger them.
Hamas took 251 hostages on 7 October 2023, in the attack that also killed about 1,200 people and triggered the war. Most hostages have been released during previous ceasefires or other deals. Israel has rescued eight hostages alive.
Of the 50 still in Gaza, Israeli officials believe about 20 are still alive.

Leo drew attention to a joint statement by the Latin and Greek Orthodox patriarchs of Jerusalem, who announced that the priests and nuns in the two Christian churches in Gaza City would stay put, despite Israeli evacuation orders ahead of the Gaza City offensive.
They said the people sheltering in the churches were too weak and malnourished to move and that doing so would be a “death sentence”.
The Holy Family Catholic church and the Saint Porphyrius Orthodox church have sheltered hundreds of Palestinian civilians during the war, including elderly people, women and children as well as people with disabilities.
Pope Francis, even during his final days in the hospital, stayed in daily touch with the parish priest of Holy Family to offer his solidarity and support to the people there, cared for by the nuns of Mother Teresa’s Sisters of Charity religious order.
In their joint statement, Catholic Cardinal Pierbattista Pizzaballa and Orthodox Patriarch Theophilos III noted that just last weekend, Leo issued a strong statement about the rights of people to remain in their homelands and not be forced to move.
“All peoples, even the smallest and weakest, must be respected by the powerful in their identity and rights, especially the right to live in their own lands; and no one can force them into exile,” Leo said in comments Saturday to a group of forced refugees from the Indian Ocean archipelago Chagos that were clearly destined for a broader audience.
Netanyahu has said Gaza’s population should be relocated to other countries through what his government has described as voluntary emigration. Rights groups have objected, and Palestinians fear that even if they leave temporarily to escape the war, Israel will never allow them to return.
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