Addressing a huge congregation at the Vatican's St Peter's Basilica, he appealed for a new understanding between Israelis and Palestinians.
Thousands of pilgrims celebrated the start of Christmas in the West Bank town of Bethlehem, amid tight security.
The Pope will deliver his Christmas Day message from St Peter's later.
Hours after the Pope spoke, Egyptian President Hosni Mubarak and Israeli foreign minister Tzipi Livni met to to discuss growing violence between Israel and militants in Gaza.
Top of the agenda was the end of the six-month ceasefire in Gaza, which the Egyptians have brokered.
'Think of the children'
Appealing for new efforts to end the cycle of violence in the Middle East, Pope Benedict urged people to pray that "hearts will be opened, so borders will be opened".
The 81-year-old pontiff plans to visit Jordan, Israel and the Palestinian territories next May, although final details of his trip have yet to be worked out.
Also in his homily, Pope Benedict appealed for an end to child abuse.
"Let us think of those street children who do not have the blessing of a family home, of those children who are brutally exploited as soldiers and made instruments of violence, instead of messengers of reconciliation and peace," he said.
"Let us think of those children who are victims of the industry of pornography and every other appalling form of abuse, and thus are traumatised to the depths of their soul.
As Midnight Mass began, Pope Benedict, dressed in white and gold-coloured vestments, walked up the main aisle of the flood-lit St Peter's Basilica, smiling and stopping several times to shake outstretched hands and bless children.
For those unable to enter, giant screens were set up in St Peter's Square.
Most of the world's 2.1 billion Christians mark Christmas this week.
Others, chiefly from among the 200 million Orthodox Christians who use the Julian Calendar for their feast days, celebrate the Nativity on 7 January.
Across the world, believers have been attending Christmas church services and, in some countries, families gathered for a traditional festive dinner at midnight on Christmas Eve.
'Explosion of love'
There was a heavy security presence in the West Bank town of Bethlehem as thousands of Christian pilgrims celebrated the start of Christmas.
Among those who attended the service in Bethlehem, which Christians believe is the birthplace of Jesus, were about 200 worshippers from the Gaza Strip whom Israel granted special permission to make the journey.
Extra Palestinian security personnel were deployed to Bethlehem from the West Bank towns of Ramallah and Jericho to safeguard visitors.
Correspondents in the town met elated pilgrims, gathering around nightfall outside the Church of the Nativity, considered the traditional birthplace of Jesus.
A dozen believers from India, Canada, Britain, the US and other countries sung impromptu renditions of Christmas carols, the Associated Press reported.
US citizen David Bogenrief, 57, played the trumpet, telling a gaggle of local children who were listening: "Jesus was the prince of peace, and he can bring that peace to you. We pray for you."
In Manger Square, vendors sold roasted peanuts and Santa Claus hats to the crowds, among whom were some local Muslims out enjoying the annual international fuss over their town.
Correspondents say a relative lull in violence in the Middle East seems to have encouraged pilgrims to return to the "Holy Land".
"Bethlehem is like the soul of the universe, and it's like an explosion of love here," said Italian fashion photographer Stefano Croce, 46.
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(Source: BBC)