Senator John Kerry, who has spent the past four years acting as an unofficial envoy for President Barack Obama, tamping down diplomatic fires around the globe, is to replace Hillary Clinton as US secretary of state.
The Senate overwhelmingly confirmed the former Democratic presidential candidate as America's top diplomat.
Tuesday's 94-3 vote marked his re-emergence on the world stage, eight years after he went down to defeat in his bid to unseat President George Bush.
Mr Kerry, 69, the son of a diplomat and a decorated Vietnam veteran, had pined for the job but was passed over in 2009. He instead became chairman of the Senate Foreign Relations Committee and Mr Obama tasked him with smoothing fractious ties with Afghanistan and Pakistan.
Mr Kerry is to be sworn in and a welcoming ceremony is planned at the State Department on Monday.
"Senator Kerry will need no introduction to the world's political and military leaders and will begin day one fully conversant not only with the intricacies of US foreign policy, but able to act on a multitude of international stages," said Sen Bob Menendez, a Democrat who will succeed Mr Kerry as committee chairman.
Sen Bob Corker, the panel's top Republican, called Mr Kerry "a realist" who would deal with unrest in Egypt, civil war in Syria, the threat of al Qaida-linked groups in Africa and Iran's pursuit of nuclear weapons.
Mr Kerry, a forceful proponent of climate change legislation, also will have a say in whether the United States moves ahead on the Keystone XL pipeline from Canada, a divisive issue that has disturbed environmentalists.