Reuters reports four people were missing following the twister, which left a trail of damage for more than 161km (100 miles).
The tornado struck Silver City, a town of 200 people in western Mississippi, as well as Rolling Fork, with a population of 1700, which was hardest hit. Parts of the state remain under tornado warning.
"At least twenty three Mississippians were killed by last night's violent tornados," Mississippi Governor Tate Reeves wrote on Twitter.
"We know that many more are injured. Search and rescue teams are still active. The loss will be felt in these towns forever."
Search and rescue teams combed through the destruction looking for survivors in Silver City and Rolling Fork.
"My city is gone, but we are resilient," Rolling Fork Mayor Eldridge Walker said on CNN. "We are going to come back strong."
Walker said several people were trapped in their homes, adding that rescue efforts were under way.
He said 12 of the people who died were in Rolling Fork. Television images showed uprooted trees, houses ripped apart and damaged motor vehicles. Many areas were without electricity.
Humphreys County Sheriff Bruce Williams told CNN that "this town has been destroyed like a bomb hit it."
Williams said there were no missing persons reported, but three deaths had been confirmed in the county.
Emergency personnel and clean up crews in Silver City, Mississippi. Photo: AFP