At least one person was killed in Tupelo, a city of about 35,000 and birthplace of Elvis Presley. Power was out in much of the city, where officials imposed an 8pm local time curfew.
Most of the deaths from the severe storm system occurred on April 27 when tornadoes tossed cars like toys in Arkansas and other states.
Monday's twister in Tupelo, one of several to tear across Mississippi, damaged hundreds of homes and businesses, downed power lines and tore up trees, the National Weather Service said.
"It was real bad. We're trying to pull people out," Tupelo Police Chief Bart Aguirre, told Reuters, referring to emergency crews going house to house, searching damaged buildings.
Some residential areas were closed off as emergency crews checked downed power lines and gas leaks.
"It's a very serious situation," said Tupelo Mayor Jason Shelton. "I am just encouraging everyone to stay inside and be weather aware. There is still a very real danger of another line coming through and people still need to be inside."
Some residents whose homes were destroyed took refuge in a Red Cross shelter at a downtown sports arena.
"I heard snapping and I said, ‘Get down on the floor!' And then the trees started falling over," said Moe Kirk Bristow, a Tupelo resident. "I haven't seen a house yet that doesn't have a tree through it or on it, so it's bad."
Reginia DeWalt described how she was woken by the tornado roaring by: "It sounded like a big pressure washer - but worse."
The storm system later pushed into parts of Alabama, where emergency officials said at least two people were killed at a trailer park near Athens, Alabama. Parts of western Georgia and Tennessee also were at risk as the system that spawned the tornadoes headed east toward the Mid-Atlantic states.
Rescue workers, volunteers and victims have been sifting through the rubble in the hardest-hit state of Arkansas, looking for survivors in central Faulkner County where a tornado reduced homes to splinters, snapped power lines and mangled trees.
Arkansas Governor Mike Beebe said at least 15 people had died statewide in the storm that authorities said produced the first fatalities of this year's tornado season.
The White House said President Barack Obama, who has been on a trip abroad, called Beebe to receive an update on the damage and to offer condolences.
Nine of the victims on April 27 came from the same street in Vilonia, a town with a population of about 4,100.
A new middle school set to open in August in the town was heavily damaged by a tractor trailer blown into its roof. A steel farm shop anchored to concrete was blown away.
Governor Beebe recounted how one woman died when the door of her home's reinforced safe room collapsed, while a father and three daughters survived by seeking shelter in a bathtub that was flipped over in winds that leveled the house.
The Arkansas National Guard was deployed to sift through the wreckage. Beebe declared a state of disaster for Faulkner and two other counties.
Medical officials reported at least 100 people in Arkansas were injured.
One person was killed in neighboring Oklahoma and another in Iowa, state authorities said.
In Georgia, Governor Nathan Deal declared a state of emergency in anticipation of the risk of storms in coming days.
"Georgia is threatened at least through tomorrow and perhaps into Wednesday," Deal said in an email sent to reporters. "We're prepared now and we'll be ready for recovery should we, God forbid, experience tornado damage or flooding."
A tornado in Baxter Springs, Kansas, that touched down on the evening of April 27 destroyed as many as 70 homes and 25 businesses and injured 34 people of whom nine were hospitalised, state and county officials said. One person was killed in Kansas, likely due to the same storm system, officials said.
The National Weather Service said the threat of tornadoes will last for several days as a strong weather system interacts with a large area of unstable air across the central and southern United States.
'Long road to healing'
"Everything is just leveled to the ground," Vilonia resident Matt Rothacher said. "It cut a zig-zag right through town."
Rothacher was at home with his wife and four children when the tornado passed through. While his home survived, The Valley Church where he serves as pastor was flattened.
Two elementary school-aged boys died in their home after having a pizza dinner at a friend's home, said Rothacher, who was helping provide grief counseling to the family that had sent the two boys home after they finished their meal as the storm approached.
The home that the boys left survived the tornado. The home the boys returned to did not, Rothacher said.
"These homes, these lives, won't be put back together anytime soon. It will be a long road to healing for these families."
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sad incident.