Leo, the first US-born pope, has repeatedly and ever more insistently called for peace in the Middle East and this week directly urged US President Donald Trump to find an "off-ramp".
"Hopefully he's looking for a way to decrease the amount of violence, of bombing," he said.
The United States and Israel sparked the war on February 28 by bombing Iran, which retaliated with strikes against Gulf states and an effective chokehold on the vital Strait of Hormuz.
"If only Trump would listen to anyone!" said Ines Duplessis, 29, who came from Paris to the Colosseum ceremony, where attendees held candles in a silence broken only by liturgical chants and recited prayers.
"For me, it's very symbolic, but nothing more," she said of the pope's appeals.
"Sadly, everything is so driven by political and economic interests" that "it's a bit of a lost cause", she said.
On Sunday, Leo will preside over Easter Mass in St. Peter's Square before delivering a typically political blessing which is especially anticipated this year.
'A form of humility'
It is the first time since 2022 that the pope has personally taken part in the Way of the Cross, which has been organised at the Colosseum since 1964.
In recent years, his predecessor Francis, who died on Easter Monday last year aged 88, had to give up attending for health reasons.
Wearing his red mozzetta and stole, Leo appeared deep in prayer during the ceremony, listening with eyes closed.
The 70-year-old pope himself carried a large wooden cross through all 14 stations retracing Jesus Christ's path to the tomb, marking a return to a tradition observed by John Paul II and Benedict XVI.
Augustin Ancel, from Paris, said the pope carrying the cross was "a powerful message".
"It's also a form of humility, because we naturally tend to see the pope as distant, as someone in a very important role," he said.
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