The drone fired two missiles at the house in Miranshah, the main town of North Waziristan Agency, Geo News channel reported.
The identity of the four persons killed in the attack could not immediately be ascertained. The house caught fire after the missiles slammed into it, local residents were quoted as saying by the channel.
This was the first US drone strike in Pakistan's tribal belt since November 17 last year.
The US had reportedly suspended its controversial drone campaign after a cross-border NATO air strike killed 24 Pakistani soldiers on November 26.
Pakistan had angrily responded to the air strike by shutting all NATO supply routes and forcing the US to vacate Shamsi airbase, reportedly used by CIA-operated drones.