Holbrooke had a central role in U.S. diplomacy for nearly five decades.
He is credited with negotiating the 1995 Bosnian peace agreement, ending that bloody conflict.
Holbrooke was nominated for a Nobel Peace Prize for his work.
Obama praised Holbrooke for making America safer.
"He is simply one of the giants of American foreign policy," Obama said earlier on Monday during a holiday reception at the State Department.
The secretary of state also commended Holbrooke for his long service when she visited him at George Washington University Hospital this weekend.
"He has given nearly 50 years of his life to serving the United States," Clinton said during a meeting in Canada.
Holbrooke received phone calls from the presidents of Afghanistan and Pakistan.
Holbrooke was born in New York in 1941 to Jewish immigrants. Right after graduating from Brown University in 1962, Holbrooke became a foreign service officer and was sent to Vietnam. He also worked as a magazine editor, professor, author and investment banker.
The Associated Press contributed to this report.
THE WHITE HOUSE
Office of the Press Secretary
For Immediate Release
December 13, 2010
Statement from the President on Richard Holbrooke
Michelle and I are deeply saddened by the passing of Richard Holbrooke, a true giant of American foreign policy who has made America stronger, safer, and more respected. He was a truly unique figure who will be remembered for his tireless diplomacy, love of country, and pursuit of peace.
For nearly 50 years, Richard served the country he loved with honor and distinction. He worked as a young foreign service officer during the Vietnam War and then supported the Paris peace talks which ended that war. As a young Assistant Secretary of State for East Asian and Pacific Affairs, he helped normalize relations with China. As U.S. Ambassador to Germany, he helped Europe emerge from a long Cold War and encouraged NATO to welcome new members.
As Assistant Secretary of State for European and Canadian Affairs, he was the tireless chief architect of the Dayton Accords that ended the war in Bosnia 15 years ago this week, saving countless lives. As Ambassador to the United Nations, Richard helped break a political impasse and strengthen our nation's relationship with the UN and elevated the cause of AIDS and Africa on the international agenda. And throughout his life, as a child of refugees, he devoted himself to the plight of people displaced around the world.
When I became President, I was grateful that Richard agreed to serve as Special Representative for Afghanistan and Pakistan. The progress that we have made in Afghanistan and Pakistan is due in no small measure to Richard's relentless focus on America's national interest, and pursuit of peace and security. He understood, in his life and his work, that our interests encompassed the values that we hold so dear. And as usual, amidst his extraordinary duties, he also mentored young people who will serve our country for decades to come. One of his friends and admirers once said that, "If you're not on the team and you're in his way, God help you." Like so many Presidents before me, I am grateful that Richard Holbrooke was on my team, as are the American people.
Earlier this evening at the State Department, I met with Richard's wife Kati and their family, David, Anthony, Lizzie, Christopher and Sarah, and I spoke to Kati after Richard's passing. I expressed to them the gratitude of the American people for his lifetime of service. They are in our thoughts and prayers tonight. Tonight, there are millions of people around the world whose lives have been saved and enriched by his work. As I said earlier this evening, the United States is safer and the world is more secure because of the half century of patriotic service of Ambassador Richard Holbrooke.