A suspected twister tore through northern Alabama, killing three people, while two people were later confirmed dead in neighbouring Tennessee.
Three children were also critically injured at a 24-hour day care centre.
The National Weather Service reported 27 tornado sightings as the storm swept through eastern Texas, Mississippi, Alabama and southern Tennessee.
Three people were killed and one person was critically injured after a tornado hit a mobile home in Rosalie, Alabama, on Tuesday night, according to Jackson County Chief Deputy Rocky Harnen.
The same twister appeared to level a closed day care centre in the Ider community in Dekalb County, injuring seven people, including three children.
The injured victims left their mobile home to seek shelter there, said Anthony Clifton, DeKalb County Emergency Management Director.
An estimated 2,400 residents were without electricity as of Wednesday morning, according to Alabama Power.
The company said that outages could increase as the storm continued to move east throughout the morning.
Officials also said dozens of buildings have been damaged or destroyed from the storms.
A couple in southern Tennessee also died after an apparent tornado swept through Polk County.
Several dozen others were injured in Tennessee, including at least 20 people in McMinn County, ABC affiliate WATE reported.
Tennessee is still reeling after four people were killed and hundreds of homes and buildings were destroyed in devastating wildfires.
More than 14,000 people were evacuated from the resort towns of Gatlinburg and Pigeon Forge.
Tornadoes and hail were also reported on Tuesday in Louisiana as well as Mississippi, where the National Weather Service in Jackson said late Tuesday that it had counted six confirmed tornadoes in the region.
Five people are dead at least a dozen injured after tornadoes and severe storms ripped through the US Southeast.