The Thursday speech, scheduled for 6:10 a.m. ET and described by aides as the continuation of a dialogue Obama began at his inauguration, will be the centerpiece of the five-day, four-country swing that features a wide range of issues and events.
Obama also will travel to Germany and France later this week.
Obama's message in Cairo is intended to reach across the wide Muslim world and continue the outreach he began with his visit to Turkey in April.
The speech gives the president the opportunity to lay out his vision for a new and improved relationship between the United States and Muslims and continue to move the ball forward on a Middle East peace process.
"There has been a breach, an undeniable breach between America and the Islamic world and that breach has been years in the making," White House Senior Adviser David Axelrod said. "It's not going to be reversed with one speech. It's not going to be revered perhaps in one administration."
Axelrod said there are "enormous consequences" for the United States and the rest of the world to launch this dialogue and the president wants it to be open and honest.
"This is not a trip that we ran though some political filter," he said. "This is a mission that the president has talked [about] throughout in terms of improving these relationships, opening up avenues of understanding between Islamic world and America so that small groups of extremists can't exploit the mistrust that's existed."
The White House hopes to get across the message that the United States and Muslims across the world share common interests on security and a range of other issues -- including economic development, health care and education.
Obama is expected to highlight his own family story, with his Muslim relatives in Kenya and his childhood experiences growing up in Indonesia, the world's most populous Muslim nation.
"The speech will outline his personal commitment to engagement based upon mutual interest and mutual respect. He will discuss how the United States and Muslim communities around the world can bridge some of the differences that have divided them," White House Press Secretary Robert Gibbs said.
White House officials said Obama asked his staff to reach out to a broad range of experts in the U.S. government, in Washington and beyond, including Muslim Americans. Officials said Obama was engaged in the speech from the beginning stages and provided all of the vision and a lot of the content.
"For the last week, he's really just been frequently holed up with his draft and editing it very heavily," said White House speechwriter Ben Rhodes.
When Obama delivers his highly-anticipated speech at the University of Cairo Thursday, its message will be aimed at the world's 1.5 billion Muslims, but because of its location, the speech is likely to focus on Muslims in the Middle East.
Obama said last week he wants to deliver "a broader message about how the United States can change for the better its relationship with the Muslim world."