One person died when an apparent twister hit the state of Georgia, overturning cars on a motorway.
Bartow County Fire Chief Craig Millsap said at least 10 cars had been flipped over on Interstate 75.
A man died in Nashville, Tennessee, when high winds toppled a tree on to a shed he had been taking shelter in.
The storm system also brought mayhem to parts of Mississippi, Arkansas, Kentucky and Indiana.
More than 60,000 customers have lost electricity from the Gulf Coast to Ohio as a result, it is estimated.
Footage showed a funnel cloud tearing through the Georgian town of Adairsville, 60 miles (97km) north-west of Atlanta.
Interstate 75 was closed in both directions after vehicles were flipped and tossed on to the grassy shoulder.
The Atlanta Journal-Constitution reports there have been numerous emergency calls of trauma and injuries.
The National Weather Service (NWS) warned of "major structure damage" in Adairsville.
Reports said people were trapped in homes and businesses and aerial news footage showed widespread damage at a factory.
Elsewhere:
The NWS is reporting golf-ball sized hail stones in some areas.
Meteorologists say warm weather from the Gulf of Mexico collided with a cold front from the west, creating volatile conditions.
A sprawling storm system has brought havoc to a swathe of the US, leaving two people dead and thousands of households without electricity.