The 87-year-old arrived in a wheelchair to preside over the mass from 10:00 am (0800 GMT) in cloudy and windy weather, with the events broadcast live around the globe.
Pope Francis urged the world to resist "the logic of weapons" in his Easter message at the Vatican on Sunday, easing growing health fears as he greeted thousands of Catholics.
The pontiff's "Urbi et Orbi" (To the City and the World) blessing came after he led Easter Mass in front of 60,000 worshippers at Saint Peter's Square while appearing in good spirits.
In his traditional speech broadcasted worldwide, Francis condemned war as "always an absurdity and a defeat," raising conflicts in Ukraine, Gaza, Sudan, Myanmar and beyond.
He renewed appeals for a ceasefire in Gaza, calling for greater aid deliveries to the devastated territory and the release of hostages taken by Hamas during its unprecedented October 7 attack on Israel that sparked the war.
The civilian population is "now at the limit of its endurance," he said, lamenting the impact on children especially.
"Let us not allow the strengthening winds of war to blow on Europe and the Mediterranean. Let us not yield to the logic of weapons and rearming," he added.
The pope prposed a "general exchange of all prisoners between Russia and Ukraine" as the war between the two countries grinds through its third year.
Francis also urged world leaders to "spare no efforts in combatting the scourge of human trafficking" to free its victims.
Moments before the blessing, Francis passed through the adoring crowd on his "popemobile" as pilgrims shouted "Long live the pope!," waved flags and strained to take pictures.
Easter Sunday marks the resurrection of Jesus Christ and is the culmination of Holy Week, a major part of the Catholic calendar followed by 1.3 billion people.
The pope on Saturday presided over the Easter Vigil at the Vatican in front of some 6,000 people from around the world, a day after his last-minute cancellation at a major Good Friday procession revived questions about his health.
He delivered a 10-minute homily in Italian, speaking without any undue difficulty and condemning "the walls of selfishness and indifference" in the world.
At the end of the two-and-a-half-hour service he showed little sign of fatigue, taking time to greet and bless some of the worshippers.
In a brief statement Friday, the Vatican had said that "to preserve his health ahead of tomorrow's vigil and the Easter Sunday mass, Pope Francis will this evening follow the Way of the Cross at the Colosseum from the Santa Marta Residence," where he lives.
Health concerns
The last-minute decision raised questions about how long Francis can continue to lead the Catholic Church.
A Vatican source told AFP on Friday there was "no particular concern" about his health and the decision to pull out had been "simply a measure of caution."
The Argentinian Jesuit had also cancelled his participation in the "Via Crucis" in 2023, but that followed a three-day hospital stay for bronchitis, and was announced well ahead of time. Weeks later, he underwent a hernia operation.
Up until Friday, the pope had attended his various engagements throughout the week, but he recently appeared tired and has sometimes delegated speaking roles to colleagues.
Francis, who never takes holidays, made his last trip in September, to the southern French city of Marseille. In December, he cancelled a much-anticipated attendance at the COP28 climate summit in Dubai.
His next scheduled trip is to Venice on April 28. The Vatican has not yet confirmed a planned trip to Asia and Pacific Ocean nations for this summer.
Francis has previously left the door open to stepping down if he can no longer do the job. That would follow the example of his immediate predecessor, Benedict XVI, who in 2013 became the first pope since the Middle Ages to voluntarily step aside.
But in a memoir published this month, Francis wrote that he did "not have any cause serious enough to make me think of resigning."
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