The US leader will visit Japan, South Korea, Malaysia and the Philippines.
The White House says the trip will focus on closer economic ties, but regional security - including China's increasingly powerful presence - is likely to dominate talks.
Asian allies are concerned over the US ability to focus on the region amid competing priorities, say analysts.
The trip was an opportunity to reinforce the importance the US placed on Asia and to re-establish ties at the leadership level, former US Assistant Secretary of State PJ Crowley told the BBC.
Continue reading the main story 23 Apr: Arrives Tokyo (evening) for dinner with Japanese PM Shinzo Abe24 Apr: In Tokyo; talks and joint press conference with Abe, state dinner25 Apr: Flies Tokyo-Seoul; talks and press conference with South Korean President Park Geun-hye26 Apr: Visit to military base; flies to Kuala Lumpur and state dinner27 Apr: Talks with Malaysian PM Najib Razak, press conference28 Apr: Flies to Manila, talks with Philippine President Benigno Aquino29 Apr: Ends visit to Philippines, returns to US"Many traditional allies... [also] value a strong US presence in the region to balance against an assertive China," Mr Crowley said.Mr Obama's visit comes amid a "period of very significant tension among American allies, and between American allies and China", he added.
'Significant tension'Mr Obama's trip - from 23-29 April - comes nearly seven months after he cancelled a visit to the region due to a government shutdown.
Stops include a private dinner with Japanese Prime Minister Shinzo Abe, as well as bilateral meetings with the South Korean, Malaysian and Philippine leaders.
The US leader is expected to balance the need to bolster US ties with each Asian nation while improving communication among them, particularly between South Korea and Japan.
The two Asian nations are at odds over disputed islands and historical issues linked to Japan's war history.
Mr Abe's views on World War Two have poisoned relations to the point where Tokyo and Seoul are now barely on speaking terms, reports the BBC's Rupert Wingfield-Hayes in Tokyo.
On Tuesday, Seoul accused Mr Abe of romanticising "Japanese colonialism and its war of aggression" after he sent an offering to the Yasukuni Shrine, where Japan's war dead - including convicted war criminals - are enshrined.
Continue reading the main storyBeijing is not on Mr Obama's itinerary this week. But as he discusses economics and security with allies in Japan, South Korea and the Philippines, China will be very much the elephant in the room and China itself will be watching closely. ”End Quote But the US - which last month brokered a meeting of the Japanese and South Korean leaders - wants the two to co-operate on North Korea, amid long-term deadlock in moves to end Pyongyang's nuclear ambitions.
On Tuesday, South Korea's defence ministry said that it had detected "a lot of activity" at the Punggye-ri nuclear test site.
North Korea could be planning to hold a "surprise nuclear test or just pretend to stage a nuclear test", a spokesman said.
A state department spokeswoman said the US was "closely monitoring the situation". The test, if it went ahead, would be North Korea's fourth.
Security allianceTies between Tokyo and Beijing will also be high on the agenda when Mr Obama touches down in Japan.
Relations are severely strained over a raft of issues, including East China Sea islands that both claim and war-linked resentments.
Japan depends on the US for its security, under a decades-old alliance that dates back to the end of World War Two.
Mr Abe wants an explicit statement of US military support over the islands, called Senkaku in Japan and Diaoyu in China.
Japan controls the islands - but Chinese ships have sailed repeatedly in and out of what Japan says are its territorial waters as Beijing presses its claim.
Continue reading the main storyMr Obama's Asia Pivot isn't supposed to be solely about geo-politics, but also a deeper rebalancing towards fast-growing Asia to boost America's economy. Securing preferential access to Asia's markets benefits US companies over Chinese firms that won't be part of the market-opening measures of the Trans-Pacific Partnership”End Quote Ahead of his visit, Mr Obama said in a written response to Japan's Yomiuri newspaper that the US opposed "any unilateral attempts to undermine Japan's administration of these islands".
The US, however, is keen for Japan to take on greater responsibility for its own security - an area where Mr Obama and Mr Abe are likely to be in general agreement.
Also of significant import is progress on the 12-nation Trans-Pacific Partnership (TPP), a trade deal which requires each country to strike an agreement with other prospective members.
A rift between Japan and the US over agriculture product tariffs has proven a major sticking point in the trade agreement.