Homes, roads and railway lines were swept away when huge hillsides collapsed as thousands of tonnes of mud was dislodged by the thunderous seismic tremors.
Buildings were reduced to rubble, including a university dormitory and apartment complexes, with dozens of people unaccounted for over a wide area.
"We are aware of multiple locations where people have been buried alive," Chief Cabinet Secretary Yoshihide Suga told a press conference.
"Police, firefighters and Self Defense Force (military) personnel are doing all they can to rescue them."
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A hospital was left teetering by Saturday morning's 7.0 quake, with doctors and patients rushed from the building in darkness.
Isolated villages in mountainous areas near Kumamoto city were completely cut off by landslides and damage to roads. At least 1,000 people were believed trapped in one settlement and expected to spend the night in public buildings, reports said.
Aerial footage showed a bridge on a main trunk road had crashed onto the carriageway below it, its pillars felled.
Adding to worries was the eruption of a nearby volcano, although seismologists cautioned there was no evidence of a link and said activity was limited.
Aftershocks continued to rock Kumamoto on Kyushu island and its surroundings, an area unaccustomed to the powerful quakes that regularly rattle other parts of Japan.
Thursday's initial quake affected older buildings and killed nine people, but Saturday's brought newer structures crashing down, including a municipal office in the city of Uto.
Nearly 1,000 people have been hurt, 184 of them seriously, she added.