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.
Obama's Cairo Speech to Focus on World's 1.5 Billion Muslims
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."
"That will require, I think, a recognition on both the part of the United States as well as many majority-Muslim countries about each other; a better sense of understanding, and, I think, the possibilities of achieving common ground," he said after a meeting with Palestinian Authority President Mahmoud Abbas at the White House.
Obama said he will emphasize the importance and contributions of Muslim-Americans in the United States, which he said is often overlooked in discussions like this.
The White House is going to great lengths to make sure Obama's speech reaches as many eyes and ears as possible, with unprecedented efforts to connect through online social networking sites.
The White House wants to reach out to the 20 million Arab Facebook users, using features on the site to promote the speech and Obama's message. The White House also plans to use MySpace, Twitter and YouTube.
The speech will be streamed live on the White House Web site and fully translated transcripts will be posted in 13 different languages.
The State Department will enable people to register to receive live text messages about the speech in four languages -- English, Arabic, Urdu and Persian -- and allow them to send feedback by text that will be posted on the department's Web site.
Middle East Peace Process Tops Agenda Early On
The speech comes as Obama juggles several critical foreign policy challenges in the region including the Israeli-Palestinian conflict, curbing Iran's nuclear ambitions, unrest in Pakistan and the wars in Iraq and Afghanistan.
Obama has met with key leaders from the region over the last several weeks, sitting down first with King Abdullah in April and then newly elected conservative Israeli Prime Minister Benjamin Netanyahu and Palestinian Authority President Abbas last month.
White House officials said that the speech will address how the United States can work with its allies in the region on these issues.
Obama is not expected to outline a detailed plan for a Middle East peace process, but he said last week that he will not shy away from making reference to the ongoing conflict between the Israelis and the Palestinians.
"Certainly the issue of Middle East peace is something that is going to need to be addressed. It is a critical factor in the minds of many Arabs in countries throughout the region," Obama said.
Polling Shows Improvement in U.S. Image in Middle East
Recent polling shows that while public opinion of the United States has improved in the Middle East, Obama still has substantial work to do to restore America's influence and reputation in the region.
New Gallup polls conducted in 10 Arab countries and the Palestinian territories show double-digit gains in the approval ratings of the United States in eight countries, including Egypt and Saudi Arabia.
Approval of U.S. leadership is up 19 points in Egypt from this time last year and 17 points in Saudi Arabia, but only a quarter of Egyptians (25 percent) and a third of Saudis (29 percent) gave the United States high marks.
White House officials said the speech should not be seen as an endorsement of Egyptian President Hosni Mubarak's government, but noted that Egypt represents the heart of the Arab world and Obama can address issues like democracy and human rights in a broad sense.
Obama will be challenged to strike a balance between addressing human rights issues and democracy in Egypt and the region while not seeming like he is imposing U.S. values or standards.
Aides said that the president would not shy away from addressing tough issues and will address concerns the administration has with parts of the Muslim world.
The White House extended invitations to dissidents and opponents of the Mubarak regime, "so the audience will be reflective of that political culture," National Security Council spokesman Dennis McDonough said.
So far, Obama does not have individual meetings set up with dissidents, but White House officials say the schedule has not been finalized.
Obama will also hold a bilateral meeting with Mubarak. The two were scheduled to meet at the White House last week but Mubarak had to cancel due to the death of his grandson.
White House officials said the Middle East will be at the top of the agenda, but the president will also not shy away from addressing civil society issues.
Cairo University will serve as a compelling backdrop for Obama's speech. The 100-year-old university has been a center of student pro-democracy protests and is a symbol of liberalism in Egypt. The university postponed exams in preparation for Obama's visit.
McDonough said that the president will directly engage young Muslims.
"Egypt is a long-time strategic ally of the United States; it's a key country in the Arab and Muslim world. It is a young -- like much of the Muslim world, itself -- is a young country with a burgeoning younger population that the president looks very much forward to engaging directly in this speech," McDonough said.
The city and university have been cleaning up in anticipation of Obama's speech.
Obama Cites 'Strategic Relationship' Between U.S. and Saudi Arabia
President Obama arrived in steamy Saudi Arabia today for the first leg of his third overseas trip, with the Middle East peace process at the top of his agenda.
In a meeting with Saudi Arabia's King Abdullah at his horse farm outside Riyadh, Obama cited the "long history of friendship" and a "strategic relationship" between the United States and Saudi Arabia.
"As I take this trip, and we'll be visiting Cairo tomorrow [Thursday], I thought it was very important to come to the place where Islam began and to seek His Majesty's counsel and to discuss with him many of the issues that we confront here in the Middle East," the president said.
King Abdullah also noted the ties between the two nations, which he said go back to the 1930's and President Franklin Delano Roosevelt and the late King Abdul-Aziz.
He endorsed Obama's election win, calling him "a distinguished man who deserves to be in this position."
As Obama arrived in Saudi Arabia, a new audio tape from Osama bin Laden emerged, accusing the U.S. president of adopting the same policies as his predecessor in the Islamic world.
Rising crude oil prices, which hit a year-high last week, have pushed up the price of gasoline. Saudi Arabia is the world's top oil exporter and is one of the top 15 trading partners of the United States, the only Muslim country on that list.
The meeting also served to further the Obama administration's efforts to build consensus and cooperation among moderate Muslim nations to work together to pressure Iran to stop their uranium enrichment program.
Obama Makes Second Trip to Europe
Later this week, Obama travels to Germany and France, his second trip to Europe as president.
On Friday, the president is scheduled to hold a bilateral meeting with German Chancellor Merkel and visit the Buchenwald Concentration Camp, which his great-uncle helped liberate in World War II.
The visit will "underscore the tragedy of the Holocaust, and will recognize the work of so many people who stopped that, including his own uncle," McDonough said.
Later that day, Obama is scheduled to visit American servicemembers at Landstuhl Regional Medical Center.
On Saturday, Obama plans to mark the 65th anniversary of the D-Day invasion with remarks at Normandy and a tour of the American Cemetery there. The president is expected to recognize the service of American veterans who will be in the audience for his speech and underscore the sacred trust the government has to veterans.
Also on the agenda is a meeting with French President Nikolas Sarkozy.
ABC News' Sunlen Miller contributed to this report.