The drone fired two missiles that hit a house adjacent to Barkat Shah Madrassa in Mir Ali area of North Waziristan Agency, security officials said.
Four persons were killed in the attack, including an Al Qaeda militant from Turkmenistan, they said. The last US drone strike in Pakistan was carried out over a month ago.
The strike came just a day after Advisor to the Prime Minister on Foreign Affairs Sartaj Aziz announced that premier Nawaz Sharif would raise the issue of drone attacks with the US on his maiden visit to Washington next month.
During a recent visit to Islamabad, US Secretary of State John Kerry had hinted that the CIA's drone campaign in Pakistan's tribal areas of Pakistan could end "very soon". However, the US administration later played down his remarks.
Kerry's remarks marked the first time that a senior US official had indicated that there could be a definitive end to the programme, which the CIA has in the past called an effective counter-terrorism weapon.
According to reports, a total of 565 militants have been killed in around 400 drone strikes in Pakistan. However, rights groups say many non-combatants have also died in these strikes.
Is the US' killing-by-drone campaign useful?
PICS: This drone can stay in the air for 4 days!
In PHOTOS: Military insect drones are here!
Whether Pak likes it or not, US drone strikes will go on
Death from 30,000 feet above