One crew member has already been rescued and is thought to be in a stable condition.
A spokesman for the Japanese Self-Defense said another crew member had been found but there were no immediate details of the marine’s condition.
“US military and the Japanese Self-Defense planes and vessels are searching for those still missing… I hope all the members will be rescued safely as soon as possible,” Iwaya added.
The marines were conducting “regularly scheduled training” when the crash occurred around 2am local time, the 3rd Marine Expeditionary Force said in a statement.
The F/A-18 fighter jet with two crew onboard and a KC-130 refuelling tanker with five crew — crashed into the sea around 100 kilometres (55 nautical miles) off the cape of Muroto in south-western Japan, Iwaya said.
The crew member rescued had been in the fighter jet, the minister confirmed.
Japan’s SDF had deployed nine aircraft and three vessels for the search, he said.
A spokesman for the Japanese coastguard said six vessels and an aircraft had been dispatched separately to assist in the rescue efforts.
There are few details about the circumstances of what the Marines described as a “mishap” and an investigation is underway.
During a normal KC-130 refuelling operation, the tanker aircraft trails a hose from the back of the plane with a so-called “drogue”, shaped a bit like a windsock, at the end.
The fighter jet then inserts a probe inside the drogue to receive fuel, which it can do at a rate of up to 3,000 pounds per minute, according to a paper prepared for the US Congress.