Almost all of Trump's senior White House officials will be travelling with him.
Saudi Arabia, the world's top oil exporter, has always been a major ally of the United States, but the relationship soured over Obama's initial reluctance getting involved in Syria and other regional problems, as well as the signing of a landmark nuclear accord and lifting of worldwide sanctions against their regional rival, Shiite Iran.
"They also grilled him on the timeline of his controversial memo that Trump used as a rationale for sacking Federal Bureau of Investigation director James Comey last week, with two senators saying Rosenstein acknowledged he knew before writing his brief that the president was going to fire Comey".
In Israel, Trump has hopes - though it is still unclear how - of reviving the moribund peace process, meeting both his "friend" Benjamin Netanyahu in Jerusalem, and Palestinian president Mahmud Abbas in Bethlehem.
Saudi Arabia adheres to an ultraconservative interpretation of Islamic law. A measure he has issued since taking office to impose a temporary travel ban on people from six Muslim-majority countries has been blocked by courts.
"Truth is, nobody knows how Donald Trump is going to act or what he's going to say in meetings of this kind because he's never done it before", summed up Stephen Sestanovich of the Council on Foreign Relations.
One leader who will not be attending the summit will be Sudan's President Omar al-Bashir. The President will also visit the Church of the Holy Sepulchre and the Western Wall.
The status of Jerusalem is one of the most sensitive and complex issues within the Middle East conflict and no country in the world now has its embassy there. By several senators' accounts, he contradicted Trump's statements that Rosenstein's written criticism of FBI Director James Comey had been a factor in Comey's recent firing by the president. Peace talks with Israel will top the agenda and Mr Trump is expected to express his support for Palestinian "self-determination".
Trump's meeting with Pope Francis - two men at odds on everything from climate change to refugee policy - remains highly unpredictable, although the pontiff says he will give America's bullish leader an open-minded hearing.
Later, Mr Trump flies to Brussels where he will be greeted by King Philippe and Prime Minister Charles Michel. "He was insane, a real nut job", the Times reported that Trump said during the May 10 meeting.
This will be closely watched after Mr Trump's conflicting pronouncements on the alliance. What we need on this trip is that kind of a showing, that when the president is in a meeting with a major leader, 'No, we're working with North Atlantic Treaty Organisation now.
Trump will end his trip with Mr Gentiloni in Sicily ahead of the G7 summit on the Italian island.
Air Force One departed Friday from Joint Base Andrews, Maryland, outside Washington, with the president, first lady Melania Trump, his daughter Ivanka and son-in-law, Jared Kushner, as well as a group of senior advisers and journalists covering the trip.