Responding to Donald Trump's claims he tolerated an Iranian bomb, Leo spoke on Tuesday before US Secretary of State Marco Rubio's two-day Vatican visit.
The Pope denied no support for Iranian nuclear arms but has opposed the US and Israeli war on Iran, drawing repeated attacks from Trump and criticism from Vice-President JD Vance.
US ambassador Brian Burch said there was no deep rift and dialogue could ease differences, while Italian Prime Minister Giorgia Meloni also criticised the Middle East war and defended the pontiff.
Can a plea for peace from the Vatican halt a superpower's war machine in the volatile Middle East?
With warships in the Strait and diplomacy in the Vatican, who will ultimately decide the fate of millions?