The raid late on Wednesday targeted a 4x4 transporting the four suspects near Mukalla, capital of Hadramawt province, with a missile leaving the vehicle charred, the official said.
Al-Qaeda in the Arabian Peninsula (AQAP), viewed by Washington as the most dangerous affiliate of the jihadist network, has controlled Mukalla since its militants overran the coastal city in April.
The United States, the only country known to operate armed drones over Yemen, has carried on with strikes on militants during months of fighting between pro-government forces and Shiite Huthi rebels.