Mehsud, who was on U.S. most-wanted terrorist lists with a $5 million bounty, is believed to have been behind a deadly suicide attack at a CIA base in Afghanistan, a failed car bombing in New York's Times Square and other brazen assaults in Pakistan that killed thousands of civilians and security forces.
The ruthless, 34-year-old commander who was closely allied with al-Qaida was widely reported to have been killed in 2010 - only to resurface later.
But a senior U.S. intelligence official said Friday the U.S. received positive confirmation that Mehsud had been killed. Two Pakistani intelligence officials also confirmed his death, as did two Taliban commanders who saw his mangled body after the strike. A third commander said the Taliban would likely choose Mehsud's successor on Saturday.
"If true, the death of Hakimullah Mehsud will be a significant blow to the Pakistani Taliban (TTP), an organization that poses a serious threat to the Pakistani people and to Americans in Pakistan," said Michael Morell, a former acting CIA director who retired in August and has championed the drone program. His comments came in a statement emailed to The Associated Press.
There is increased tension between Islamabad and Washington over the drone attacks, and Pakistan is also trying to strike a peace deal with the Taliban.
The group's deputy leader was killed in a drone strike in May, and one of Mehsud's top deputies was arrested in Afghanistan last month.
The intelligence officials and militant commanders said Friday's drone attack that killed Mehsud hit a compound in the village of Dande Derpa Khel in the North Waziristan tribal area. Four other suspected militants were killed, they said, including Mehsud's cousin, uncle and one of his guards. They did not have the identity of the fourth victim.
At least four missiles struck just after a vehicle in which Mehsud was riding had entered the compound, the Taliban commanders said, adding that a senior group of militants was discussing the peace talks at a nearby mosque shortly before the attack.
All the officials and the militant commanders spoke on condition of anonymity because they were not authorized to talk to the media.
The CIA and the White House declined to comment.
Pakistan's tribal region is dangerous to visit, making it difficult for journalists to independently confirm information on drone attacks there.
The Pakistani government was swift to condemn the drone strike, although that comment came before news of Mehsud's death was reported.
"These strikes are a violation of Pakistan's sovereignty and territorial integrity. There is an across the board consensus in Pakistan that these drone strikes must end," the Ministry of Foreign Affairs said in a statement.
It's a particularly sensitive time for the government, which has been trying to cut a peace deal with the militants to end years of fighting in northwestern Pakistan.
During a visit Thursday to London, Pakistani Prime Minister Nawaz Sharif said talks with the Pakistani Taliban had started, though he gave no other details.
Sharif met with President Barack Obama in Washington on Oct. 23 and pressed him to end the strikes. The U.S. has shown no sign that it intends to stop using what it considers a vital tool to fight al-Qaida and the Taliban.
The attacks are extremely unpopular in Pakistan, where many people view them as an infringement on Pakistani sovereignty and say too many innocent civilians are killed in the process. Pakistani officials regularly criticize the strikes in public, although the government is known to have secretly supported at least some of the attacks.
Popular politician Imran Khan has been one of the most vocal critics of the strikes. His party runs the government in northwest Khyber Pakhtunkhwa province and has threatened to block trucks carrying supplies to NATO troops in Afghanistan unless the attacks stop.
Officials from parties seen as more sympathetic to the Taliban, including Khan's, criticized Friday's attack, saying it was a deliberate attempt by the U.S. to sabotage the peace process.
Others in Pakistan will likely cheer Mehsud's death because of the pain and suffering he has brought to the country.
The youngest of four children, Mehsud attended school until the 8th grade, when he began pursuing a religious education at an Islamic seminary.
He gained a reputation as a ruthless planner of deadly suicide attacks while serving as the Pakistani Taliban's military chief.
The U.S. National Counterterrorism Center described him as "the self-proclaimed emir of the Pakistani Taliban."
After taking over as the Pakistani Taliban's leader, he tried to internationalize the group's focus. He increased coordination with al-Qaida and Pakistani militants, such as Lashkar-e-Jhangvi, and funded the group's many attacks by raising money through extortion, kidnapping and bank robbery.
In November 2008, he offered to take reporters on a ride in a U.S. Humvee seized from a supply truck heading to Afghanistan.
Mehsud was on the FBI's most-wanted terrorist list and has been near the top of the CIA Counterterrorism Center's most-wanted list for his role in the December 2009 suicide bombing that killed seven Americans - CIA officers and their security detail - at Forward Operating Base Chapman in Khost, Afghanistan. The suicide bomber, a Jordanian double agent, was ushered into the military base to brief CIA officers on al-Qaida, and detonated his explosive vest once he got inside the base.
Mehsud later appeared in a prerecorded video alongside the Jordanian, who said he carried out the attack in retribution for the death of another former Pakistani Taliban leader, Baitullah Mehsud, who was killed by an American drone in 2009.