Flying back to Washington from Florida, Trump used a lengthy social media post to sharply criticise Leo, then kept it up in comments on the tarmac to reporters.
"I'm not a fan of Pope Leo," he said.
Trump's comments came after Leo suggested over the weekend a "delusion of omnipotence" is fuelling the US-Israel war in Iran.
While it's not unusual for popes and presidents to be at cross purposes, it's exceedingly rare for the Pope to directly criticise a US leader - and Trump's stinging response is equally unusual.
"Pope Leo is WEAK on Crime, and terrible for Foreign Policy," the president wrote in his post, adding, "I don't want a Pope who thinks it's OK for Iran to have a Nuclear Weapon".
He repeated that sentiment in comments to reporters, saying, "we don't like a pope who says it's OK to have a nuclear weapon".
Leo presided over an evening prayer service in St Peter's Basilica on Saturday, local time, the same day the United States and Iran began face-to-face negotiations in Pakistan during a fragile ceasefire.
The Pope didn't mention the United States or Trump by name, but his tone and message appeared directed at Trump and US officials, who have boasted of American military superiority and justified the war in religious terms.
Leo, who is set to leave on Monday for an 11-day trip to Africa, has previously said God "does not listen to the prayers of those who wage war, but rejects them".
He's also referenced an Old Testament passage from Isaiah, saying "even though you make many prayers, I will not listen - your hands are full of blood".
Before the ceasefire, when Trump warned of mass strikes against Iranian power plants and other infrastructure and warned that "an entire civilisation will die tonight", Leo described such sentiments as "truly unacceptable".
In his social media post on Sunday night, US time, Trump went far beyond the war in Iran in criticising Leo.
"I don't want a Pope who thinks it's terrible that America attacked Venezuela, a Country that was sending massive amounts of Drugs into the United States," the president wrote.
"I don't want a Pope who criticises the President of the United States because I'm doing exactly what I was elected, IN A LANDSLIDE, to do," Trump added, referencing his 2024 election victory.
He also suggested in the post that Leo only got his position "because he was an American, and they thought that would be the best way to deal with President Donald J. Trump".
"If I wasn't in the White House, Leo wouldn't be in the Vatican," Trump wrote.
"Leo should get his act together as Pope, use Common Sense, stop catering to the Radical Left, and focus on being a Great Pope, not a Politician. It's hurting him very badly and, more importantly, it's hurting the Catholic Church!"
In his comments to reporters, Trump remained highly critical, saying of Leo, "I don't think he's doing a very good job".
"He likes crime I guess," Trump said, adding, "he's a very liberal person".
In the 2024 election, Trump won 55 per cent of Catholic voters, according to AP VoteCast, an extensive survey of the electorate.
However Trump's administration has close ties to conservative evangelical Protestant leaders and has claimed heavenly endorsement for the war on Iran.
Defence Secretary Pete Hegseth urged Americans to pray for victory "in the name of Jesus Christ".
And, when Trump was asked whether he thought God approved of the war, he said, "I do, because God is good - because God is good and God wants to see people taken care of".
