Search crews scrambled to dig through rubble looking for people trapped under collapsed buildings.
The magnitude-6.2 quake struck near Ueki, the U.S. Geological Survey said. Dozens of smaller aftershocks followed.
"The ground shook for about 20 seconds before the 6.2-magnitude quake stopped," witness Lim Ting Jie said.
Two deaths occurred in Mashiki, the Kumamoto Prefecture office said. One person died in a collapsed house, and the other died in a fire caused by the quake. Journalist Mike Fern told CNN that scores of buildings had either collapsed or caught fire, while the tremors triggered landslides, tore up roads and in one case, derailed a bullet train.
Nearly 800 people were injured, 50 severely. The prefecture office said 44,449 people had evacuated.
Prime Minister Shinzo Abe told parliament early Friday that he'd mobilized 3,000 members of Japan's Self Defense Force, police and fire service to join the rescue effort overnight. He said the government is "racing against the clock and will provide more personnel if necessary."
Gen Aoki, director of the Japan Meteorological Agency's earthquake division, warned more aftershocks could occur over the next week.
"This is an earthquake that is going to shake for a long time," CNN meteorologist Chad Myers said.
That could mean many more building collapses.
"The buildings that were damaged in the original shock have now been redamaged or reshaken," he said. "And all of a sudden you have a cracked building, and it wants to fall down with the second shake."
Robert Geller, a seismologist at Tokyo University, said the quake increases the likelihood of eruptions from Mount Aso, Japan's largest active volcano -- though there have been no reports of extra activity, according to the Meteorological Agency.
An estimated 750,000 people felt "violent to severe shaking," Myers said.
"The strongest shaking was right where the most people live" in the area, he said.
While the magnitude might not seem extreme, the shallow depth of the quake -- just 10 kilometers (6.2 miles) -- is significant.
"When you have a shallow earthquake, such as this one is, you have the potential for more damage because the shaking is close to the surface," John Bellini of the U.S. Geological Survey said.
In addition to destroying 19 houses, the quake hurled items off store shelves and littered streets with rubble.
But there's one bit of good news: The quake was centered mostly under land, not an ocean, meaning it did not spawn a major tsunami.
Regulators also moved to allay fears around the country's nuclear plants, with the country's only facility currently online in Sendai unaffected. The Genkai plant, which is located on Kyushu, also reported no problems.
A high-risk area
Japan, which sits along the so-called Ring of Fire, is no stranger to earthquakes.
The largest recorded quake to hit Japan came on March 11, 2011, when a magnitude-9.0 quake centered 231 miles (372 kilometers) northeast of Tokyo devastated the country.
That quake triggered a massive tsunami that swallowed entire communities in eastern Japan. It caused catastrophic meltdowns at the Fukushima Daiichi nuclear power plant.
The disaster killed about 22,000 people -- almost 20,000 from the initial quake and tsunami, and the rest from health conditions related to the disaster.
Jie said Thursday's quake gave him a new appreciation for life.
"This experience has helped me to treasure my family members and relatives even more, and not take what I have and the people who support me for granted."