While tangible goals for both the Israel and Saudi Arabia visits are still in progress, senior White House officials said the trip will serve as an opportunity to make strides in defense and diplomacy.
From Rome, Trump will travel to Brussels for a North Atlantic Treaty Organisation summit and then to Sicily for a meeting of the Group of Seven economic powers.
"If and when the Vatican is attacked by ISIS, which as everyone knows is ISIS's ultimate trophy, I can promise you that the pope would have only wished and prayed that Donald Trump would have been president because this would not have happened", Trump said in a statement past year.
In Saudi Arabia, a White House official said Trump would meet with Saudi and other Arab leaders.
As of April, the White House had not approached the Holy See for an audience with the pope during Trump's trip.
On Thursday in a rare public address Jared Kushner, H.R. McMaster, and Dina Powell shared the details behind President Trump's first foreign visit which will include a trip to Israel, Saudi Arabia, and the Vatican.
Although the kingdom is a long-time U.S. ally, Trump will be the first president since Jimmy Carter not to visit Canada or Mexico first.
The meeting will likely be watched closely by many, especially given Trump's penchant for speaking his mind and Francis' habit of making off-the-cuff comments that are often controversial.
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Riyadh and Washington had a testier relationship under former Democratic president Barack Obama's administration, which Saudi Arabia felt placed less importance on the Saudi-US relationship than on securing a nuclear deal with Iran.
"We will not allow people of faith to be targeted, bullied or silenced again and we will never stand for religious discrimination", Trump said.
The formal announcement of the visit said Trump would meet with Palestinian Authority President Mahmoud Abbas during the trip, but did not say where he would meet him.
This is the latest into a term that a president has waited to travel outside the country since Lyndon B. Johnson in 1964.
Relations between the pope and Trump suffered a serious blow previous year when the Republican candidate pledged to build a wall on the U.S.
"I think what the president has demonstrated already and will be able to demonstrate further on this trip is that 'America First' is fully compatible with American leadership in the world", the official said.
Last month he met with the Saudi Deputy Crown Prince, Mohammed bin Salman, at the White House, and in February he played host to the Israeli Prime Minister Benjamin Netanyahu. During the campaign, when asked about Trump's border wall with Mexico, Francis famously said anyone who wants to build a wall is "not Christian".
Trump later softened his tone, saying the pope was misinformed, unaware of the impact of the drugs coming into the United States and a range of security issues that made it necessary to build a wall along the southern USA border.