Trump can expect a warm reception when he arrives in the oil-rich kingdom for talks with King Salman, but the domestic mood was grim following news that the FBI's investigation into his campaign's ties with Russia extends to a current senior White House official.
Former FBI director James Comey has agreed to publicly testify about the probe, piling pressure on the White House as fresh allegations emerged about Trump calling him a "nut job" in a meeting with Russian Foreign Minister Sergei Lavrov last week and saying his sacking had relieved "great pressure".
Before departing, the president tweeted he would be "strongly protecting American interests" on his marathon eight-day trip to the Middle East and Europe, that presents a major diplomatic test.
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While his predecessor Barack Obama was viewed with suspicion by Gulf Arab states for his tilt towards their Shiite regional rival Iran, Trump is likely to take a harder line against Tehran.
That, together with a more muted focus on human rights and the likely announcement of new arms deals, should please Washington's traditional Sunni Gulf allies.
"He's going to be tougher on Iran," said Philip Gordon, senior fellow at the Council on Foreign Relations.
"He's not going to lecture them on democracy and human rights," he added.
Ahead of Trump's visit to Saudi Arabia, where he will be accompanied by his wife Melania and daughter Ivanka, Washington and Riyadh issued their first "joint terrorist designation" - blacklisting a leader of the Iranian-backed Lebanese armed Shiite movement Hezbollah.
Late Friday, Saudi Arabia announced it had shot down a ballistic missile fired by Yemeni rebels southwest of Riyadh.
The US provides weapons, intelligence and aerial refuelling to the Saudi-led coalition fighting the Huthi rebels, who are backed by Iran and oppose the government of Yemen President Abedrabbo Mansour Hadi.
'Muslim ban'
Trump's relations with the wider Islamic world are still strained by his travel ban targeting several Muslim-majority nations.
So all eyes will be on a speech on Islam that the president is scheduled to deliver to dozens of Muslim leaders at a summit in Riyadh on Sunday.
"I'll speak with Muslim leaders and challenge them to fight hatred and extremism, and embrace a peaceful future for their faith," Trump said ahead of his visit.
Trump wants Gulf states in particular to do more to tackle extremists such as the Islamic State jihadist group.
"He will encourage our Arab and Muslim partners to take bold, new steps to promote peace and to confront those, from ISIS to Al-Qaeda... who perpetuate chaos and violence that has inflicted so much suffering throughout the Muslim world and beyond," said Trump's National Security Adviser HR McMaster.
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While most US presidents make their first foreign trip to neighbouring Canada or Mexico, 70-year-old Trump has opted for six stops.
He will hold countless face-to-face meetings including with Pope Francis and France's new leader, Emmanuel Macron.
It is a trip fraught with peril for the real estate magnate, who is known to dislike lengthy travel.
The avalanche of revelations in the run-up to his departure have eroded Trump's standing at home - where the parallels with Richard Nixon's ill-fated presidency are now being openly drawn.
On Friday, a report by The Washington Post that the probe into his campaign's Russia ties had identified a "significant person of interest" in the White House, undercut Trump's insistence his election bid had nothing to do with the Kremlin.
The White House was rocked by another bombshell when reports emerged that Trump said his firing of "nut job" Comey had relieved "great pressure" on him due to the investigation.
The scandals have revived questions about his ability to strike a presidential tone with his foreign counterparts, with Trump declaring himself the victim of the "greatest witch hunt" in American political history.
Arms contracts
His visit to the Gulf is expected to bring lucrative arms contracts for US firms.
"The big question mark that you should bear in mind is if Saudi Arabia signs up for a $100 billion arms deal with oil prices where they are today, how are they actually going to pay that in the future?" said Bruce Riedel, former CIA analyst and counterterrorism expert now with the Brookings Institution.
After Saudi Arabia, Trump will head to Israel and the Palestinian Territories where he hopes to revive the moribund peace process.
He will meet his "friend" Israeli Prime Minister Benjamin Netanyahu in Jerusalem and Palestinian president Mahmud Abbas in Bethlehem.
The Israeli leg of his trip is already awash in controversy - from a row over Trump's visit to Jerusalem's Western Wall, the holiest prayer site for Jews, to his alleged disclosure of Israeli intelligence to Russian officials.
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.
The president will also meet members of the North Atlantic alliance in Brussels and attend a G7 summit in the picturesque Sicilian town of Taormina overlooking the Mediterranean.
