Francis, who two days ago branded a military solution in Syria "a futile pursuit," led the world's 1.2 billion Roman Catholics in a global day of prayer and fasting for peace in Syria, the Middle East and the world.
"Violence and war lead only to death, they speak of death! Violence and war are the language of death!" Francis said at the midpoint of a five-hour prayer service. Police and the Vatican estimated a crowd of about 100,000 in St Peter's Square.
The United States and France are considering military action against Damascus to punish President Bashar Assad for an Aug. 21 chemical weapons attack in Syria's civil war that killed hundreds of people. Assad's government denies responsibility.
A number of people held up Syrian flags and placards reading "Hands off Syria," and "Obama, you don't have a dream, you have a nightmare." But they were not allowed into St Peter's Square, in keeping with the pope's intention for a religious service.
The service was punctuated by music, prayer, the reciting of the rosary and long periods of silence in which the participants were asked to meditate on the need for peace to vanquish the destruction of war.
"We have perfected our weapons, our conscience has fallen asleep, and we have sharpened our ideas to justify ourselves. As if it were normal, we continue to sow destruction, pain, death!" said Francis, who wore his simple white cassock instead of ceremonial robes to the service.
"At this point I ask myself: Is it possible to change direction? Can we get out of this spiral of sorrow and death? Can we learn once again to walk and live in the ways of peace?"
He then asked "each one of us, from the least to the greatest, including those called to govern nations, to respond: Yes, we want it!"
When he announced the prayer vigil last Sunday, Francis asked Catholics around the world to pray and fast and invited members of other religious to take part in any way they saw fit in the hope that a wider war could be averted.
"That's very scary, very scary," said Lennie Tallud, a clinical lab scientist visiting St Patrick's Cathedral in New York. Asked whether she thought prayers would make a difference, she said: "Definitely, for sure. No doubt. I think it would - 100 percent."
Services were held by Christians around the world, including in Jerusalem, Assisi and Milan in Italy, in Boston and Baghdad.
Muslims pray with pope
Yaha Pallavicini, a leader of Italy's Muslim community, attended the prayer service with other Muslims.
"Praying for the intention of peace is something that can only help fraternity and, God willing, avoid more war," he told Reuters. "As Muslims who want peace we have to work so that the values of faith and dialogue prevail over the destruction of peoples."
In his address, the pope, who for most of the service sat silently behind an altar on the steps of the largest church in Christendom, stressed the power of prayer to change the world.
"This evening, I ask the Lord that we Christians, and our brothers and sisters of other religions, and every man and woman of good will, cry out forcefully: violence and war are never the way to peace!" he said.
"Let everyone be moved to look into the depths of his or her conscience and listen to that word which says: Leave behind the self-interest that hardens your heart, overcome the indifference that makes your heart insensitive towards others, conquer your deadly reasoning, and open yourself to dialogue and reconciliation," he said.
His words struck a personal chord with Marina Verkotenh, a pilgrim from Russia. "I think it's very important for all the people to unite here at this square and to bring together all our forces to unite and to pray, and also to bring attention to all the people who decide this question, these important questions about war and peace," she said.
At least one senior U.S. clergyman publicly expressed reservations about President Barack Obama's campaign for military action against Syria.
"As Congress debates a resolution authorising military force in Syria, I urge you instead to support U.S. leadership for peace. Only dialogue can save lives and bring about peace in Syria," Miami Archbishop Thomas Wenski said in a message sent to U.S. senators from Florida and to his representative in the U.S. House of Representatives.