Secretary of State John Kerry will accompany the president on his visit, although the First Lady Michelle Obama is expected to stay home.
After touching down at Tel Aviv's Ben Gurion Airport, Obama will be greeted by Israeli President Shimon Peres and Prime Minister Binyamin Netanyahu before touring the Iron Dome anti-missile defence system, which the US provided funding to develop.
The Iron Dome was recently put to the test during Israel's skirmish with Palestinians in Gaza late last year.
Topics on the table will include Israel's growing tensions with Iran, as well as ongoing discussions over the Palestinian territories.
Obama will also travel to the West Bank where he'll meet with Palestinian leaders, including Palestinian Authority President Mahmoud Abbas, in the city of Ramallah as well as Palestinian youths.
Deputy National Security Advisor for Strategic Communications Ben Rhodes says the "true purpose" of the visit will be an appearance at the Jerusalem Convention Centre, where he'll give a speech to an audience of mainly Israeli university students on Thursday night.
The President will then visit Jordan and meet with King Abdullah, where conversation is expected to turn to Syria and the estimated 360,000 refugees who have crossed the border from the stricken country since January 2012.
The trip will end with a visit to the Jordanian world heritage-listed site of Petra.
