The Missouri State Highway Patrol reported that two adults were killed in the Bakersfield area in Ozark County and multiple people were injured.
The deaths come as a massive storm system moving across the country unleashed winds that damaged buildings, whipped up deadly dust storms and fanned more than 100 wildfires.
Extreme weather conditions — including hurricane-force winds — are forecast to affect an area home to more than 100 million people.
Winds gusting up to 130 km/h were predicted from the Canadian border to Texas, threatening blizzard conditions in colder northern areas and wildfire risk in warmer, drier areas to the south.
"Numerous significant tornadoes, some of which should be long-track and potentially violent, are expected this afternoon and evening," the National Weather Service said Saturday.
Three people were killed Friday in car crashes during a dust storm in Amarillo County in the Texas Panhandle, according to Sergeant Cindy Barkley.
One pile-up involved an estimated 38 cars.
"It's the worst I've ever seen," Barkley said, calling the near-zero visibility a nightmare.
"We couldn't tell that they were all together until the dust kind of settled."
Evacuations were ordered in some Oklahoma communities as more than 130 fires were reported across the state.
The State Patrol said winds were so strong that they toppled several large trucks.
"This is terrible out here," said Charles Daniel, a truck driver hauling 14.6-metre trailer along Interstate 40 in western Oklahoma.
"There's a lot of sand and dirt in the air. I'm not pushing it over 55 mph. (88 km/h) I'm scared it will blow over if I do."
Forecasters said the severe storm threat would continue into the weekend with a high chance of tornadoes and damaging winds on Saturday in Mississippi and Alabama.
Heavy rain could bring flash flooding to some parts of the East Coast on Sunday.
Experts say it's not unusual to see such weather extremes in March.
"What's unique about this one is its large size and intensity," said Bill Bunting of the National Weather Service's Storm Prediction Centre in Norman, Oklahoma.
"And so what that is doing is producing really substantial impacts over a very large area."
The weather service said at least five tornadoes were reported in Missouri on Friday, including one in the Saint Louis area. Several buildings were damaged.
The Storm Prediction Centre said fast-moving storms could spawn twisters and hail as large as baseballs, but the greatest threat would come from straight-line winds near or exceeding hurricane force, with gusts of 160 km/h possible.
The Storm Prediction Centre said parts of Mississippi including Jackson and Hattiesburg and areas of Alabama including Birmingham and Tuscaloosa would be at a high risk.
Severe storms and tornadoes were also possible across eastern Louisiana, western Georgia, central Tennessee and the western Florida Panhandle.
Wildfires in the Southern Plains threatened to spread rapidly amid warm, dry weather and strong winds, and evacuations were ordered Friday for some communities in Texas, Oklahoma, Kansas, Missouri and New Mexico.
High winds also knocked out power to more than 300,000 homes and businesses in Texas, Oklahoma, Arkansas, Missouri, Illinois and Indiana.
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