The Central Investigation Agency-operated spy plane fired two missiles at the house in the remote Shawal area near the Afghan border on Tuesday, officials in the region said on Tuesday night.
Shawal is located 200 km from Miranshah, the main town of North Waziristan Agency.
Four militants were killed and two others injured in the strike, the officials were quoted as saying by the media.
The US has continued drone strikes in Pakistan's tribal belt despite Islamabad's condemnation of the attacks. Pakistan has described the drone attacks as counter-productive for the war on terror, saying they provoke anti-US sentiments.
US officials claim the drone campaign is effective in targeting the Al Qaeda and Taliban elements hiding in North Waziristan.
The US has significantly increased drone strikes in Pakistan since a North Atlantic Treaty Organisation Summit in Chicago ended last month without a deal on ending Islamabad's six-month blockade of supply routes to Afghanistan.
The supply lines were shut after a cross-border NATO air strike killed 24 Pakistani soldiers in November last year.
On June 4, a drone attack killed 15 militants in North Waziristan. The dead included senior Al Qaeda leader Abu Yahya al-Libi.
Pakistan summoned the acting US envoy on June 5 and lodged a strong protest over the drone strikes, saying the attacks were unlawful and a violation of the country's sovereignty.