Church services were to be held throughout the stricken region as stunned Americans grappled with the magnitude of the destruction wrought by Friday's twisters.
President Barack Obama called the governors of Indiana, Kentucky and Ohio to offer condolences for the dead and said the federal emergency management agency was ready to help, the White House said.
Deaths were reported in Indiana, Kentucky, Ohio, Alabama and Georgia as the storm system moved east.
"The scope and magnitude of devastation in some of our communities is unlike anything I have ever seen," said Kentucky governor Steve Beshear, whose office confirmed 19 fatalities from over a dozen tornadoes that roared across the state.
Trucks and trees were upended as the deadly funnels ravaged parts of eight states in the Midwest and south.
A school bus smashed through the wall of a house, trucks were thrown into lakes, solid brick homes were reduced to rubble and wooden ones smashed into kindling. Mobile homes were flipped like tin cans.
About 300 injuries have been reported in Kentucky, according to Beshear, who surveyed the damage in the devastated town of West Liberty. There was damage in 40 counties and power supplies to tens of thousands were knocked out.
Amateur video aired on CNN showed a gargantuan grey twister churning over West Liberty on Friday as a woman loudly prayed, "Oh God, take it away from us Lord!"
At least 14 people were killed in Indiana, according to governor Mitch Daniels, who inspected the devastation in Henryville.
"We're not unfamiliar with Mother Nature's wrath out here in Indiana but this is about as serious as anything I've seen in my years in this job," an emotional Daniels said. "Lucky it wasn't worse."
He said that early warning systems had probably saved lives.
Clark County, Indiana, had to deal with widespread damage after roads were blocked by fallen trees and debris, and power and phone lines were knocked out.
The hardest-hit town was Marysville, a small town that has all but ceased to exist, officials said.
"That's the information we have - that Marysville is no longer," US Senator Dan Coats of Indiana told CNN.
The only good news amid all the death and devastation was a report that a two-year-old girl survived a terrifying tornado that killed her parents and siblings.
The unidentified toddler was found lying among the bodies of her family in a field near a flattened home in New Pekin, Indiana, said hospital staff.
"She is still in critical condition," Cis Gruebbel, a nurse at Kosair Children's Hospital, in Louisville, Kentucky, said.
Indiana activated 250 members of its National Guard, who used Black Hawk helicopters to reach hard-hit regions. Indiana and Kentucky declared states of emergency.
There were three deaths in neighbouring Ohio, including a city councillor from the town of Moscow, an Emergency Management Agency official said.
The Gulf coast state of Alabama reported one death after tornadoes trapped people in rubble, destroyed houses and uprooted trees.
For Brandy Robbins, whose home in Harvest, Alabama, was destroyed in tornadoes last year, it was a sickening case of deja vu.
"I realised lightning does strike twice," she told Fox News, outside the home she recently rebuilt, only to have it badly damaged again.
"Unfortunately, my kids and I are going to have to rebuild again."
In Georgia, a woman was killed in the city of Alpharetta, north of Atlanta, and tornadoes severely damaged at least 40 homes and a regional airport west of the city.
The latest wave of storms hit as people were picking through rubble left behind by a string of twisters across six states that killed 13 people earlier in the week.
Just R20 for the first month. Support independent journalism by subscribing to our digital news package. 
