The Pope Francis is traveling to Amman, where he will celebrate Mass in a stadium, and later meet Syrian refugees.
The official purpose of the visit is to improve ties with the Orthodox Church.
However, correspondents say many will expect Pope Francis to use his influence to try to ease tensions in the region.
Pope Francis will be accompanied by a rabbi and an imam – friends from his native Argentina – and hopes to improve relations between Christians, Muslims and Jews in the Holy Land.
His journey comes only a few weeks after the latest round of Israeli-Palestinian peace talks collapsed.
Israel has issued restraining orders against several Jewish right-wing activists this week over concerns that they could try to disrupt the visit.
Police said offensive “anti-Christian graffiti” was discovered on the wall of a church in the southern city of Beersheba on Friday.
Pope Francis’ journey marks the 50th anniversary of the historic meeting in Jerusalem between Pope Paul VI and the head of the Orthodox Church, Patriarch Athenagoras.
The meeting ended 900 years of separation and enduring antagonism between the Eastern and Western branches of Christianity.
On Sunday, Pope Francis will travel to Bethlehem in the West Bank and preside over Mass in Manger Square, near the site where Jesus is believed to have been born.
He will also meet the current Ecumenical Orthodox Patriarch, Bartholomew, and they will sign a declaration of friendship.
The pontiff’schedule on Monday is set to include a visit to the al-Aqsa mosque complex in Jerusalem’s Old City followed by the Dome of the Rock and the Western Wall.
Pope Francis will be the fourth leader of the Roman Catholic Church to visit Jerusalem, after Popes Paul VI, John Paul II and Benedict XVI, who went there in 2009.
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