Umer Farooq, believed to be in charge of al-Qaeda's operations in Pakistan and Afghanistan, was killed in the strike that took place in the Khar Tangi area of Datta Khel district in the region, where the Pakistani military has been battling Taliban and al-Qaeda-linked militants since June.
A security official said Farooq was among five people killed when two missiles fired from the drone hit a compound.
Also known Umer Ustad and Ustad Farooq, he was also working as al-Qaeda chief for Afghanistan and Pakistan.
His killing came a day after Pakistani forces killed top al-Qaeda operative Adnan Shukrijuma in raid at a house in South Waziristan.
The chief of al-Qaeda's global operations, Shukrijuma was wanted by the US over a 2009 plot to attack the New York subway system.
Shukrijuma was among the five men indicted in the US over the plot to bomb New York's subway system under orders from al-Qaeda leaders in Pakistan.
The New York indictment links him to the Manhattan plot and a similar never-executed scheme to attack British subways, according to media reports.
The Pakistani military launched a major offensive in North Waziristan in June and say they have killed more than 1,000 militants so far.
For almost a decade, American drone strikes in Pakistan's tribal belt have been deeply unpopular with the public.
Pakistani officials have publicly condemned the drone strikes, saying they violate sovereignty.
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