Mr Obama travels first to Saudi Arabia and then to Egypt, where he will make a keynote speech on ties with the region.
He says he wants to open dialogue with Muslims and overcome misapprehensions on both sides. He also wants to revive Middle East peace negotiations.
It is his first Middle East visit since taking office.
Barack Obama's goal is to improve perceptions of the US and to push for a peace deal between Israel and the Palestinians, says BBC Diplomatic Correspondent Jonathan Marcus.
In the process he wants to make other US strategic goals in the region - like stability in Iraq and the containment of Iran - easier to achieve.
To do this he needs Arab partners and this trip takes in two key nations - Saudi Arabia and Egypt.
The Saudis are sponsors of the only comprehensive peace plan for relations between the Arab world and Israel.
Egypt is intimately involved with the Palestinian problem, acting as an intermediary between Israel and Hamas in the Gaza Strip.
Mr Obama needs both countries on board if he is to breathe life into the largely moribund peace negotiations, our correspondent says.
'Action not words'
In Saudi Arabia, Mr Obama will hold talks with King Abdullah in Riyadh. As well as regional issues, Mr Obama said he would raise the issue of oil prices with the Saudi ruler.
On Thursday, he is to deliver a speech at Cairo University which he hopes will set a new tone in US-Arab relations.
After Cairo, Mr Obama will travel on to Europe for D-Day commemorations.
The tour itinerary does not include Israel but shortly before departing for Saudi Arabia, Mr Obama had a meeting with Israel's defence minister, Ehud Barak, in Washington.
The president is reported to have used the meeting to reiterate that the US intends to be tough with Israel on the question of settlement building in the West Bank.
Israel is resisting calls to freeze building activity in all settlements, but Palestinian leaders have said there can be no progress towards peace without a halt to such construction.
Speaking to the BBC ahead of his visit, Mr Obama said he believed the US was "going to be able to get serious negotiations back on track" between Israel and the Palestinians.
He said his visit offered the US and the Islamic world the chance "to listen to each other a little bit more".
But there were no silver bullets, he warned.
"There are very real policy issues that have to be worked through that are difficult. Ultimately, it's going to be action and not words that determine the path, the progress from here on out," he said.
On the eve of his visit, the deputy leader of al-Qaeda urged Muslims to ignore the new tone from Washington.
In an audio message posted on a website, Ayman al-Zawahiri said Mr Obama's "bloody messages" - in Iraq and Afghanistan - would not be concealed by "polished words".
