Mehsud's second wife and his bodyguards were killed in the air raid in Makeen, a difficult-to-access village in the tribal heartland near the border with Afghanistan.
A US official in Washington, speaking anonymously, also said there was "some reason to believe Mehsud may be dead" but added that "it can't be confirmed at this time".
Neither the Pakistani nor US governments have confirmed the attack because of sensitivities over violation of Pakistan's territorial sovereignty.
The US and Pakistan say Mehsud is linked to al-Qaeda and has been involved in dozens of suicide attacks, beheadings and assassinations, including the killing of Benazir Bhutto, the former Pakistani prime minister.
The US has placed a $5m bounty on Mehsud's head and branded him "a key al-Qaeda facilitator" in Pakistan's tribal belt.
A relative of Mehsud's dead wife had initially said the Taliban leader was not present when the missile struck, but rumours that he had either been wounded or killed refused to die down.
A senior Pakistani security official said that aside from Mehsud's wife, one of Mehsud's brothers and seven of his bodyguards perished in the attack.
The official said intelligence services were trying to learn the identity of another victim, and there was a good chance that it was Mehsud.
Mehsud declared himself leader of the Pakistan Taliban, grouping around 13 factions in the northwest, in late 2007.
His estimated 10,000-20,000 fighters have been blamed for a wave of suicide attacks inside Pakistan and on Western forces across the border in Afghanistan.