The renewed violence "threatens the desired climate of trust and mutual respect needed to resume dialogue between Israelis and Palestinians", the Pope said as he addressed a crowd of tens of thousands gathered in Saint Peter's Square.
There has been a surge in Israeli-Palestinian violence over the past week as the Muslim fasting month of Ramadan, Jewish Passover and Christian Easter coincide.
On Wednesday, Israeli police stormed the Al Aqsa mosque, Islam's third-holiest site, in a predawn raid aimed at dislodging "lawbreaking youths and masked agitators" they said had barricaded themselves inside.
The next day, more than 30 rockets were fired from Lebanese soil into Israel, which the Israeli army blamed on Palestinian groups, saying it was most likely Hamas, which rules the Gaza Strip.
Israel then bombarded Gaza and southern Lebanon, targeting "terror infrastructures" that it said belonged to Hamas.
On Friday, two separate attacks left an Italian tourist and two British-Israeli sisters dead, and several injured, in Tel Aviv and the West Bank.
On Sunday, Israel launched strikes on Syria in retaliation for rockets the army said were fired from there towards Israel.
The Pope also invoked prayers for the Ukrainian and Russian people and praised nations the welcome refugees as he ended the Easter celebrations with the traditional speech known as ”Urbi et Orbi", which means “to the city and the world”.
Since Russia invaded neighbouring Ukraine in February 2022, Francis has repeatedly called for the fighting to end and sought prayers for the “martyred” Ukrainian people.
“Help the beloved Ukrainian people on their journey towards peace, and shed the light of Easter upon the people of Russia,'' he said in his address from the central balcony of St Peter's Basilica. ”Comfort the wounded and all those who have lost loved ones because of the war, and grant that prisoners may return safe and sound to their families."
He urged the international community to work to end the war in Ukraine and “all conflict and bloodshed in the world, beginning with Syria, which still awaits peace.” Francis also prayed for those who lost loved ones in an earthquake that struck Syria and Turkey two months ago, claiming tens of thousands of lives.
But Francis also noted progress on some fronts.
“Let us rejoice at the concrete signs of hope that reach us from so many countries, beginning with those that offer assistance and welcome to all fleeing war and poverty," he said, without naming any particular nations.
The bloody conflicts cited by Francis contrasted with a riot of bright colours lent by orange-red tulips, yellow sprays of forsythia and daffodils, hyacinths and other colourful seasonal flowers that decorated St Peter's Square. The blooms brought in by lorry from the Netherlands and set up in planters to decorate the square.
Some 45,000 people had gathered by the start of the midmorning Mass, according to Vatican security services, but the crowd swelled to about 100,00 before the pontiff's address.
Still recovering from bronchitis, Francis, 86, had skipped the traditional Good Friday procession at Rome’s Colosseum due to unseasonably cold night-time temperatures.
Francis has generally rebounded following a three-day stay last week at a Rome hospital where he was administered antibiotics intravenously for bronchitis. He was discharged on April 1.
But near the end of the more than two-hour-long Easter Sunday appearance, he seemed to start running out of steam. His voice grew hoarse and he interrupted his speech at one point to cough.
With reporting from agencies