"There are very few moments in our lives where we have the privilege of witnessing history taking place," Obama said. "This is one of those moments."
The anti-government protesters' voices "have been heard and their country will never be the same," Obama said.
Mubarak, 82, announced he would resign Friday, one day after he said he would remain in office until after elections are conducted in September. Anti-government protesters have been demonstrating since Jan. 25, seeking Mubarak's ouster.
Obama pledged the United States would be a partner for Egypt and provide assistance if asked.
The ouster of Mubarak didn't mark the end of a transition, but a beginning that would experience difficulties along the way, Obama said.
"I am confident the people of Egypt can (find) the answers … peacefully and constructively," Obama said. "Nothing less than genuine democracy will carry the day."
The Supreme Council of Egyptian Armed Forces, which Obama said served responsibility as a caretaker of the people, must ensure the transition is credible now that Mubarak designated it to run the country.
The council will be tasked with making changes that are irreversible and providing a "clear path to elections that are free and fair," Obama said.
He said the spirit of peaceful protests "can serve as a powerful wind" and expressed hope that the enthusiasm, ingenuity and spirit of Egypt's youth could be harnessed to help create jobs as the country moves forward.
The events in Egypt are a testament to "the power of human dignity" and the peacefulness put "the lie to the idea that justice is best gained through violence," Obama said.
"Non-violence (is) the moral force that bent the arc of history toward justice once more," Obama said. "The entire world has taken note."