The landmark trip to Obama's ancestral homeland of Kenya, where his father was born, is his first as president and is also the first time a sitting US president will visit Ethiopia and the AU's headquarters in Addis Ababa.
The first African-American president of the United States is expected to address regional security issues, and also touch on matters relating to trade, democracy, poverty and human rights in the region.
Joining him on the trip is National Security Adviser Susan Rice, foreign policy aide Ben Rhodes and White House spokesman Josh Earnest.
Obama has visited Africa four times while in office, but has not yet travelled 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 organisations 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.