Holbrooke, whose government career spanned nearly five decades and ranged from junior diplomat in South Vietnam to serving as the U.S. ambassador to Germany and at the United Nations, passed away after surgery to repair a tear in his aorta.
He fell ill on Friday during a meeting with Clinton and was taken to a Washington hospital, where he underwent hours of extensive surgery to try to save his life.
"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," President Barack Obama said in a statement.
"He was a truly unique figure who will be remembered for his tireless diplomacy, love of country, and pursuit of peace," Obama added, noting that Holbrooke had served as an assistant secretary of state both for East Asian and European affairs.
"He was the consummate diplomat, able to stare down dictators and stand up for America's interests and values even under the most difficult circumstances," said Secretary of State Hillary Clinton.
A tenacious diplomat who earned a reputation as a "bulldozer" in negotiating the 1995 Dayton Accords that concluded the Bosnian war, Holbrooke was once called "Washington's favorite last-ditch diplomat" by Time magazine.
Nominated for the Nobel Peace Prize seven times, Holbrooke joined Obama's administration in January 2009 as special representative for Afghanistan and Pakistan, dealing with two of Washington's most vexing foreign policy challenges.
Nine years after the U.S. invasion that toppled the Taliban rulers in Afghanistan, there are nearly 100,000 U.S. troops in the country battling an insurgency that has been fortified by its ability to find safe havens in neighboring Pakistan.
Analysts do not expect Holbrooke's death to have much impact on a report due this week on Obama's build-up of forces in the Afghanistan war. The U.S. strategy is meant to allow Afghan security forces to gradually take over and permit American troops to start withdrawing in July 2011.
DAYTON ACCORD WAS HIGH POINT
Seen as one of the United States' most can-do diplomats, Holbrooke had a strained relationship with Afghan President Hamid Karzai, who held on to power in presidential elections last year that were marred by widespread reports of fraud.
Some analysts believe Holbrooke achieved mixed results at best on U.S. policy toward Afghanistan and Pakistan and that his influence had waned. He may be best remembered for bringing the warring parties in Bosnia to terms.
"The Dayton agreement was the high point of his achievements and I think it was a turning point in the Clinton administration's foreign policy," said James Dobbins, another U.S. diplomat who served with Holbrooke at the Paris peace talks on ending the Vietnam War.
Holbrooke was sometimes known in the Balkans as "Raging Bull" and "The Bulldozer" because of the forceful tactics and cajoling he used to get opposing sides to the negotiating table at an air base in Dayton, Ohio, while serving as an assistant secretary of state under President Bill Clinton.
Known for his blunt diplomatic style, Holbrooke was quoted by the BBC as saying he had no qualms about negotiating with "people who do immoral things."
"If you can prevent the deaths of people still alive, you're not doing a disservice to those already killed by trying to do so," he said. "And so I make no apologies for negotiating with Milosevic and even worse people, provided one doesn't lose one's point of view."
In between his stints in government, Holbrooke had a varied career that included time as an editor of Foreign Policy magazine, as a managing director at Wall Street firm Lehman Bros, and as an author.
Holbrooke wrote "To End a War," his account of the Balkan conflict and his efforts to end it, and was co-author on "Counsel to the President," the memoirs of U.S. lawyer Clark Clifford who played an important role in the presidencies of Harry Truman, John F. Kennedy and Lyndon Johnson.