Hakimullah Mehsud, who was believed to be in his mid-30s and was one of Pakistan's most wanted men, has been reported dead several times before.
But late on Friday, several intelligence, army and militant sources across Pakistan confirmed he had been killed in the drone strike in the lawless North Waziristan region.
"We can confirm Hakimullah Mehsud was killed in the drone strike," said one senior security official.
Mehsud's Pakistani Taliban is an umbrella of militant groups separate to but allied to the Afghan Taliban.
Mehsud took over the Pakistani Taliban in August 2009 after a drone strike killed the previous leader, his mentor.
Four security officials confirmed his death to Reuters. His bodyguard and driver were also among the dead, they said.
"Among the dead, who are in large numbers, are Hakimullah's personal bodyguard Tariq Mehsud and his driver Abdullah Mehsud, two of his closest people," said one intelligence source, adding at least 25 people were killed in the strike.
There was no official comment from the government or from the Taliban.
Earlier, regional sources said drones had fired four missiles at a compound in Danda Darpa Khel, a village about 5 km (3 miles) from the regional capital of Miran Shah, killing at least four people.
North Waziristan is the stronghold of the Taliban insurgency and shares a border with Afghanistan.
The U.S. offered $5 million for Mehsud's capture after he appeared in a farewell video with the Jordanian suicide bomber who killed seven CIA employees at a base in Afghanistan in 2009.
U.S. prosecutors have charged him with involvement in the attack.
The killing is the latest in a series of setbacks for the Pakistani Taliban. A drone strike killed Mehsud's number two in May and one of his most trusted lieutenants was captured in Afghanistan last month.
The death follows months of debate over potential peace talks between the Taliban and the new government of Pakistani Prime Minister Nawaz Sharif, who swept to a landslide victory in May elections.