The strike 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 that five people were killed when two missiles fired from the drone hit a compound.
The compound was completely destroyed in the attack.
One of the dead was identified as Umer Farooq who served as al-Qaeda’s spokesman in Pakistan.
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 Pakistan 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.
North Waziristan has long been used as shelter by the Taliban and al-Qaeda-linked militants and has frequently been targeted by US drones.
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.