The severe weather killed 128 people in Alabama on Wednesday, April 27 alone, authorities said, and President Barack Obama said Washington would be rushing search and rescue assistance to the battered southeastern state.
States of emergency were declared in Alabama, Arkansas, Kentucky, Mississippi, Missouri, Tennessee and Oklahoma, and governors called out the National Guard to help with rescue and cleanup operations.
The National Weather Service (NWS) had preliminary reports of more than 300 tornados since storms began Friday, including more than 130 yesterday alone.
Alabama was especially badly hit, caught by two lines of storms and an evening tornado that tore through the city of Tuscaloosa, home to the University of Alabama.
Tuscaloosa Mayor Walter Maddox told CNN that the tornado had "obliterated blocks and blocks" of his city.
"My wife and I were watching the weather coverage until the monster was right up on us," Tuscaloosa resident Will Nevin told The Birmingham News, the local newspaper.
"Then it was the mad dash to the bathroom where the lights flickered, pulsed and finally gave up." A tornado also struck the city of Birmingham and officials were still assessing the damage.
"This has been a very serious and deadly event that's affected our state, and it's not over yet," Alabama Governor Robert Brantley told reporters after the second string of storms.
The NWS issued a rare "high-risk" warning of tornados, hail, flash flooding and dangerous lightning for parts of Alabama, Georgia and Mississippi.
It warned that severe weather could also strike 21 states from the Great Lakes down to the Gulf Coast and across to the Atlantic, and tornados were reported as far east as Virginia and Maryland.
Storm victims across the region were trapped in homes, trailers and cars by falling trees. Hail the size of golf balls cracked windows.
Roads were washed out or rendered impassable by fallen trees and power lines across the region. Homes, schools and businesses were flattened, flooded and set on fire by lightning.
"Our citizens have endured days of consecutive severe storms and flooding," said Kentucky Governor Steve Beshear.
"We stand ready to assist any community in need, and we urge Kentuckians to remain on alert until this storm system finally passes."