Pope Francis on Sunday made a "pressing appeal" against a "spiral of violence" after Iran's unprecedented missile and drone attack on Israel, warning of a potential regional conflagration.

"I make a pressing appeal for an end to any action which could fuel a spiral of violence that risks dragging the Middle East into an even greater conflict," the Argentinian pontiff declared following his traditional Sunday prayer in Saint Peter's Square at the Vatican.

"I am praying and following with concern, but also pain, the news that has come in recent hours about the worsening situation in Israel due to Iran's intervention," the pope told worshippers.

"No one should threaten the existence of others. All countries must, however, side with peace and help Israelis and Palestinians to live in two states, side by side and in security," he said. 

"That is their right," Francis insisted as he once again repeated earlier calls for a ceasefire in Gaza and "negotiation."

The pontiff furthermore demanded the world "help the population facing a humanitarian crisis” in Gaza and urged the "immediate release of the hostages kidnapped months ago" by Hamas, setting in train the latest chapter of violence in the region.