President Barack Obama announced late Wednesday he had approved Alabama Gov. Robert Bentley's request for emergency federal assistance, including search and rescue support.
"While we may not know the extent of the damage for days, we will continue to monitor these severe storms across the country and stand ready to continue to help the people of Alabama and all citizens affected by these storms," Obama said in a statement.
At least one strong tornado swept through Tuscaloosa, Alabama, leaving dozens of roads impassable and destroying hundreds of homes and businesses.
"It literally obliterated blocks and blocks of the city," Mayor Walter Maddox said, describing Tuscaloosa's infrastructure as "decimated."
Witnesses also reported tornado touchdowns in Birmingham, Alabama.
"It looked like it was probably a mile wide," Birmingham Mayor William Bell said.
The northwest corner of the city was particularly devastated, he said, with hundreds injured and many others missing.
Red Cross spokesman Chris Osborne said the number of ambulances on the street in Birmingham, "is just like taxicabs in New York."
"It's just back and forth to area hospitals," Osborne said. "It's really just an incredible sight to see."
Osborne said Pratt City and Pleasant Grove were among the hardest hit areas.
"It's just bare land, debris everywhere," Cierra Brown, of Jefferson County, Alabama, told CNN affiliate WBMA about her devastated neighborhood. "There's no house."
"My bathroom is across the street," Talesha Oliver told WBMA.
Henry Nguyen told CNN early Thursday he was working at his father's convenience store on the edge of Pratt City when he saw a twister angling for the front door. He ducked. When he stood up, Nguyen said he saw that the tornado had missed the storefront by 50 yards.
"Houses are gone. It's pretty crazy," Nguyen said. "A gas station up the street is gone. There is nothing else open here."
Several meteorological conditions combined Wednesday to create a particularly dangerous mix, CNN meteorologist Sean Morris said.
"It is tornado season, but an intensive event like this only will occur maybe once or twice a year," he said. "It's very rare to have all these ingredients come together."
Reports of people trapped in homes or overturned vehicles were coming in from every state in the region, according to emergency management officials.
Hundreds of thousands of people across the region were without power, including 269,000 in Birmingham, said Michael Sznajderman, a spokesman for Alabama Power.
"We're chipping away" at restoring power, he said, but crews may be forced to halt work as a second line of storms approach.
At least 18 people were killed in storm-related incidents in Mississippi on Tuesday night and Wednesday, according to the state Emergency Management Agency. Among the fatalities was a 3-year-old girl in McComb, Mississippi, who died in her bed from a falling tree.
"Our thoughts and prayers are with the families who lost loved ones or property in this devastating storm," said Mississippi Gov. Haley Barbour, who declared a state of emergency in 39 counties. The declaration allows the state to offer aid to the counties during recovery efforts.
The state was also bracing for flooding along the Mississippi River.
The storms killed 11 people in Georgia. Seven were killed in Catoosa County and two in Dade County, according to the Georgia Emergency Management Agency. The storms claimed two additional victims in Spalding County, according to the local sheriff's office.
The town of Ringgold, Georgia, was hit particularly hard.
The Georgia storms left as many as 54,000 customers without before dawn Thursday, according to utility spokesman Jeff Wilson
The storm also unleashed as many as 80,000 chickens in Pickens County, Georgia, after four of their houses were destroyed.
Georgia Gov. Nathan Deal declared disaster areas in four other northwestern counties.
Deal declared a state of emergency in Catoosa, Floyd, Dade and Walker counties.
Arkansas and Tennessee reported that at least one person died in each of those states.