A twister hit Little Rock, Arkansas, at 2:25pm local time (19:25 GMT) on Friday afternoon, following severe storm and tornado warnings.
Widespread damage to buildings and houses across the city has been reported, with cars left overturned on the streets and almost 70,000 homes without power in the central Arkansas area.
At least a dozen people have been injured and one person confirmed dead, authorities said.
The town of Wynne in northeastern Arkansas was also devastated, and officials reported two dead there, along with destroyed homes and people trapped in the debris.
There were more confirmed twisters in Iowa, damaging hail fell in Illinois and wind-whipped grass fires blazed in Oklahoma, as the storm system threatened a broad swath of the country home to some 85 million people.
At least seven dead as devastating twisters rip through several US statesGovernor of Arkansas Sarah Huckabee Sanders has declared a state of emergency and has tweeted that officials are working to assist the injured.
She has also confirmed she has activated the state's national guard. The state-based military force are called to respond to emergencies such as natural disasters.
"They will be assisting Arkansas State Police and local law enforcement around the state," she wrote.
The tornado was reported to hit the west of Little Rock first, hurtling through neighbourhoods and hitting a small shopping centre and grocery store.
It then passed over to the north of the city, across the Arkansas River, where it caused severe damage to residences, several businesses and vehicles.
Passengers and staff at Little Rock’s Clinton National Airport were reportedly told to take shelter in bathrooms until 3:45pm.
The Little Rock Fire Department has confirmed they have been performing rescue operations across the city and have reported heavy damage and debris in the west.
The University of Arkansas for Medical Sciences Medical Center in Little Rock, has confirmed it is expecting at least 15-20 patients from the tornado, with spokeswoman Leslie Taylor stating that it was operating at a mass casualty level.
Baptist Health Medical Center, the state's biggest hospital, said it was preparing for a surge of patients.
Spokeswoman Cara Wade said: "We have already begun to receive patients, and a few of these are in critical condition."
Gran's dashcam footage from inside tornado that struck her car on way homeBill Bunting, the operations chief for the Storm Prediction Center has warned that there could be more tornados to come.
Speaking to the BBC, he said: "At the moment, things are unfortunately playing out just as we have feared.
"I think the next couple of hours are unfortunately going to be very active with severe thunderstorms, tornadoes and intense damaging straight-line winds.
"We believe the tornadoes will be on par with what we saw last week. The question is, will they track? And what structures will be in their path? And that will largely determine the impact."