In Kentucky, 14 people were killed by severe weather and the death toll is likely to rise, according to Governor Andy Beshear.
Local authorities in Laurel County, in the state's southeast, said nine people were killed after a tornado touched down.
Laurel County resident Chris Cromer said he got the first of two tornado alerts on his phone about 11.30pm or so, about a half-hour before the tornado struck.
He and his wife grabbed their dog, jumped in their car, went to a relative's nearby home and got into a crawl space.
"We could hear and feel the vibration of the tornado coming through," said Cromer, 46.
His home is intact although a piece of the roof got ripped off and windows were broken.
A house two doors down is destroyed, along with others in the Sunshine Hills neighbourhood, Cromer said.
"It's one of those things that you see on the news in other areas, and you feel bad for people - then, when it happens, it's just surreal," he said, describing a landscape of destruction.
"It makes you be thankful to be alive, really."
Rescuers were searching for survivors all night and into the morning, the sheriff's office said.
An emergency shelter was set up at a local high school and donations of food and other necessities were arriving.
The National Weather Service had not yet confirmed that a tornado struck but meteorologist Philomon Geertson said it was likely.
It ripped across the largely rural area and extended to the London Corbin Airport shortly before midnight.
"Lives have been changed forever here tonight. This is a time we come together, and we pray for this community," London mayor Randall Weddle told WKYT-TV.
The latest Kentucky storms were part of a weather system on Friday that killed seven in Missouri and two in northern Virginia, authorities said.
The system also spawned tornadoes in Wisconsin, brought a punishing heat wave to Texas and temporarily enveloped parts of Illinois - including Chicago - in a pall of dust on an otherwise sunny day.
"Well that was .... something," the weather service's Chicago office wrote on X after issuing its first-ever dust storm warning for the city.
Thunderstorms in central Illinois had pushed strong winds over dry, dusty farmland and northward into the Chicago area, the weather agency said.
In Missouri, St Louis mayor Cara Spencer on Friday confirmed five deaths in her city and said more than 5000 homes were affected.
"This is truly, truly devastating," Spencer said.
An overnight curfew was imposed on Friday in the most damaged neighbourhoods.
Hospitals in the area reported receiving dozens of patients, with some in serious condition.
Weather service radar indicated a likely tornado touched down between 2.30pm and 2.50pm in Clayton, Missouri, in the St Louis area.
The apparent tornado touched down in the area of Forest Park, home to the St Louis Zoo and the site of the 1904 World's Fair and Olympic Games the same year.
