One of his first initiatives was to end the U.S. focus on poppy eradication in Afghanistan, on the grounds that removing the livelihood from opium production that sustained many Afghan farmers was counterproductive.

Mr. Holbrooke crossed swords with another part of the administration in Pakistan, where he ordered an end to the automatic renewal of aid contracts with U.S. and other foreign nongovernmental organizations with long histories there.

He experienced health problems in August, when he underwent treatment for heart problems and canceled one of his frequent trips to Afghanistan and Pakistan. On Friday morning, he was taken to George Washington University Hospital after he became flushed and suffered chest pains during a meeting with Clinton.

As he was sedated for surgery, his final words were to his Pakistani surgeon, according to family members: “You’ve got to stop this war in Afghanistan.”