Speaking to reporters on a flight to Algeria, the first American pope said too many innocents were being killed and someone had to stand up.
His remarks answered attacks from US President Donald Trump that pulled him into arguments over the Iran war and immigration policy.
The exchange has set Vice-President JD Vance and Secretary of State Marco Rubio against American Catholic voters, while Leo's intervention follows a long papal tradition of addressing global conflict.
Is the first American Pope's moral stance on the Iran war a new model for global spiritual leadership?
When a Pope and President clash over a major war, whose authority will ultimately shape the global narrative?