Obama left Andrews Air Force Base at 10:30 am (1430 GMT) aboard Air Force One, on a trip that was first to make a stopover in Washington state to visit the scene of a deadly landslide.
From there, the president's itinerary was to take him to Japan, South Korea, Malaysia and the Philippines.
The visit is Obama's fifth to the region during his presidency.
During his travel, Obama will attempt to make progress in dragged out negotiations over the Trans Pacific Partnership (TPP) trade deal, and reassure potential partners that he can get it endorsed by a reluctant Congress.
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In Seoul, Obama will hold talks with South Korean President Park Geun-Hye that focus on North Korea's belligerence. The US president will also attempt to ease tensions between Seoul and Tokyo.
Obama will then travel to Malaysia, where he will become the first US president to visit since Lyndon Johnson traveled there in 1966 as part of an Asian tour designed to check the spread of communism.
Obama begins his Malaysia program with a state dinner on April 26.
In one of the keynote moments of the trip, he also will host a town hall style meeting with young leaders across Southeast Asia at Malaya University.
On April 28, Obama will head to the Philippines for talks with President Benigno Aquino. He is scheduled to hold a joint press conference with Aquino, and be the guest of honor at a state dinner.
The US president will also lay a wreath at the World War II American cemetery.
China is not on the president's itinerary but is expected to loom large throughout his Asia visit, because of its enormous reach as a regional economic and political behemoth.