At a special prayer vigil in St Peter's Basilica, the first US pope decried the use of religious language to justify war and said a "delusion of omnipotence that surrounds us ... is becoming increasingly unpredictable".
He made a direct appeal to world leaders.
"Stop! It is time for peace! Sit at the table of dialogue and mediation, not at the table where rearmament is planned," he said.
Leo, who is known for choosing his words carefully, has emerged as an outspoken critic of the Iran war.
On Saturday, he used forceful language to denounce conflict, citing letters from children in war zones he said described "horror and inhumanity".
The pope also referenced the church's opposition to the 2003 US-led invasion of Iraq, citing an appeal by the late Pope John Paul II made four days before the start of that conflict.
"Enough of the idolatry of self and money!" Leo said.
"Enough of the display of power! Enough of war!"
The pope, who on March 30 said God rejects the prayers of leaders who start wars and have "hands full of blood," denounced again on Saturday the use of Christian language to justify war.
"The balance within the human family has been severely destabilised," said Leo.
"Even the holy name of God, the God of life, is being dragged into discourses of death."
The pope's earlier comments were interpreted by conservative Catholic commentators as aimed at US Defence Secretary Pete Hegseth, who has invoked Christian language to justify the joint US-Israeli strikes on Iran that initiated the war.
Saturday's special prayer service was announced by Leo last Sunday, in the pope's Easter message.
