The first African-American president of the United States is expected to address regional security issues and trade, and also touch on matters relating to democracy, poverty and human rights in the region.
Joining him on the trip is National Security Advisor Susan Rice, foreign policy aide Ben Rhodes and White House spokesman Josh Earnest.
Before heading off on the trip - Obama`s fourth time to Africa since taking office - he spoke about the promise, and difficulties, on the continent.
"Despite its many challenges - and we have to be clear-eyed about all the challenges that the continent still faces - Africa is a place of incredible dynamism, some of the fastest-growing markets in the world, extraordinary people, extraordinary resilience," Obama said ahead of the trip.
He said Africa "has the potential to be the next center of global economic growth," speaking at an event for the African Growth Opportunity Act, US trade legislation which aims to help bolster Africa`s prosperity.
Obama has traveled to Africa more than any other sitting US president, and talked about the "deep" ties between Africa and the United States before setting off on the trip.
"There have been times where there have been misunderstandings, and there have been times where there have been suspicions. But when you look at every survey, it turns out that the people of Africa love the United States and what it stands for," he said.
Obama has not yet been to Kenya during his White House tenure, with a previous trip delayed by Kenyan President Uhuru Kenyatta`s indictment for war crimes by the International Criminal Court.
Those charges were suspended last year - in part, prosecutors say, because the Kenyan government thwarted the investigation.
His trip has also come under fire by rights groups, and more than 50 African and global human rights organizations have called on him to publicly meet democracy activists on the trip.
They voiced concerns about "grave and worsening" rights challenges in both Kenya and Ethiopia.
The charges against Kenyatta, and the fact Ethiopia`s government won 100 percent of parliamentary seats in a recent disputed election, has raised questions about whether Obama should have made the trip at all.
In Kenya, Obama will attend a Global Entrepreneurship Summit, aimed at promoting businesses that promise to lift many more Africans out of poverty and help insulate societies against radicalization.
In Addis Ababa, Obama is expected to address leaders of the African Union, remarks that may touch on Africa`s democratic deficit.
There are no official visits scheduled for Obama to see his relatives while in Kenya, officials said.
Obama has said he had "never truly known" his father, was born in Kenya`s far west, in a village near the equator and the shores of Lake Victoria.
A pipe-smoking economist, he walked out when Obama was just two and died in a car crash in Nairobi in 1982, aged 46.
Obama has previously made personal visits to Kogelo, the home of many of his Kenyan relatives, most recently in 2006.
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