The line of storms, which stretched from Arkansas northeastward into Ohio, produced dozens of tornadoes and heavy rains that forecasters say could last for days.
Western Tennessee was particularly hard-hit by the system, with state and local authorities reporting on Thursday at least five deaths across several counties.
A father and his teenage daughter were killed in Tennessee's Fayette County when their modular home was overturned by a tornado, local media reported, citing the sheriff's office.
Three others were hospitalized, including the mother, who was extracted from the home wreckage by emergency responders.
Photos shared on social and local media showed widespread damage from the storm across several states, with homes torn apart, toppled trees, downed power lines and overturned cars.
"A multi-day, potentially historic heavy rainfall event may produce catastrophic and life-threatening flooding through Saturday," the National Weather Service (NWS) said.
Other deaths were reported in Indiana -- where a man was reportedly electrocuted after his car hit a downed power line -- and Missouri, with the Perryville Fire Department saying a nearby district's fire chief "made the ultimate sacrifice" in an unspecified storm-related incident.
Schools were closed in various areas impacted by the storm, including Tennessee's state capital Nashville.
Before the storm's arrival in Kentucky, Governor Andy Beshear warned residents that the state was "facing one of the most serious weather events we've had forecast."
Damaging winds and isolated tornadoes were possible into Thursday night, warned the NWS in Louisville, the state's largest city.
As of Thursday, electricity was out for around 230,000 customers across the central-eastern United States, according to the PowerOutage.us website.
A variety of damaging weather is expected in the coming days.
"All modes of severe weather will be possible" the NWS office in Little Rock, Arkansas reported Thursday, including "very large hail, strong gusty winds and even a few tornadoes."
Warning of "unsettled weather" the NWS in Lincoln, Illinois, posted on X that severe storms, including hail and damaging wind gusts, were possible into Friday.
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