The northwest area, rife with Islamist extremist networks, has been the focus of a barrage of bombings in the past month by US spy planes, as Washington targets militant groups it says Pakistan is failing to tackle.
The morning attack by a drone aircraft struck a vehicle carrying suspected militants in Ghundikala village, 15 kilometres (nine miles) east of Miranshah, the main town of North Waziristan and close to the Afghan border.
"A US drone fired two missiles, targeting a vehicle and killing three militants," a senior security official in the area told AFP.
"The identity of militants is not known yet. It is also not clear whether any high value target was present in the area when the attack took place."
Another security official confirmed the strike and the casualties. Both officials requested anonymity because of the sensitivity of the US strikes in Pakistan, which have inflamed anti-American sentiment.
It was not clear which group was targeted, with North Waziristan rife with Taliban militants, Al-Qaeda fighters and members of the Haqqani network, a powerful group known for staging attacks on foreign troops in Afghanistan.
The bombing comes the morning after a similar US drone attack killed four militants in Machikhel village, about 25 kilometres east of Miranshah, with officials suggesting some of the dead were Al-Qaeda operatives.
Seven US missile strikes in the same area of North Waziristan have killed 44 people in the past month, although the identities of those killed are hard to verify as the deaths are deep in Taliban-controlled territory.
The region last year saw a rise in US strikes after US President Barack Obama took office and put the country on the frontline of the war on Al-Qaeda.
The attacks on Pakistani territory fuel anti-Americanism in the nuclear-armed Muslim nation and the government in Islamabad publicly condemns the strikes, although analysts say they give the US tacit approval.
More than 70 US drone missile strikes have killed at least 662 people in Pakistan since August 2008. The US does not confirm drone attacks, but its military is the only force that deploys pilotless drones in the region.
North Waziristan neighbours South Waziristan, where Pakistan has been focusing its most ambitious military offensive yet against homegrown Taliban militants, sending about 30,000 troops into the region on October 17.
Obama's administration is pressuring Islamabad to crack down on not only the Pakistani Taliban, but also Al-Qaeda fighters and militants who cross the border and attack US and NATO forces stationed in Afghanistan.
He has put Pakistan at the heart of his new strategy for winning the eight-year war against the Taliban in neighbouring Afghanistan, saying success depends of the dismantling of militant sanctuaries along the porous frontier.