On Tuesday, a US missile strike pulverised a compound in South Waziristan, killing up to 16 people.
Wednesday's attack was the fifth in two weeks against Mehsud and his followers in his stronghold of South Waziristan.
Top Arab leaders of the al-Qaeda network are believed to be hiding in the region, as well as scores of fighters from nearby countries, especially Afghanistan and Uzbekistan.
The US is thought to have launched more than 40 missiles against targets in the border area since last August, according to a count by The Associated Press news agency.
One attack on the funeral of a dead fighter killed up to 80 people.
Pakistan's army is deploying troops in South Waziristan and launching regular air strikes of its own to try and kill or capture Mehsud, who is blamed for organising many of the suicide attacks in Pakistan over the last few years.