The Oklahoma chief medical examiner's office said there were at least 51 confirmed deaths, MSNBC reported. NBC News said at least 20 of those were children.
"It is absolutely devastating, this is horrific," Oklahoma Lt. Gov Todd Lamb said. "We're going to have fatalities. ... We're going to have significant injuries. ... We just don't know what those numbers are. Schools have been hit, a hospital has been hit, businesses have been flattened, neighborhoods have been wiped away -- we don't have the numbers in yet, but it is going to be significant and it is going to be horrific."
President Obama spoke by phone with Oklahoma Gov. Mary Fallin to express his concern for the victims of the storms that ravaged the state both Monday and Sunday, the White House said in a statement.
"While information is still coming in, the president made clear that his administration, through FEMA [the Federal Emergency Management Agency], stands ready to provide all available assistance as the governor's team responds to the storm, and that he has directed his team to ensure that they are providing available resources as the response unfolds," the White House said.
"The president told Governor Fallin that the people of Oklahoma are in his and the first lady's thoughts and prayers and, while his team will continue to keep him updated, he urged her to be in touch directly if there were additional resources the administration could provide."
One sixth-grade boy named Brady told KOCO-TV he and other children at Briarwood Elementary School in Moore took refuge in a bathroom.
"Cinderblocks and everything collapsed on them but they were underneath so that kind of saved them a little bit, but I mean they were trapped in there," he said.
Neighbors pulled children and teachers out of the rubble at Plaza Towers Elementary School in Moore.
KFOR reported Plaza Towers Elementary students hugged and clung to school walls as the tornado passed.
ABC said area hospitals received dozens of people with injuries, including 33 at Integris Southwest Medical Center in downtown Oklahoma City where officials said 10 were in critical condition.
Oklahoma University Medical Center spokesman Scott Coppenbarger said the facility had received 20 patients.
KFOR-TV, Oklahoma City, reported the dead included a 7-month-old baby.
KWTV-DT, Oklahoma City, cited unnamed reports as saying three people had died at a 7-Eleven Store in Moore.
CNN said the tornado was estimated to be 2 miles wide as it swept through the southern suburb of Moore. Its affiliate, KFOR-TV, reported houses were leveled. KOKH-TV, Oklahoma City, reported the National Weather Service said the storm was at least an EF-4, meaning winds hit 200 mph.
"It's just destroying everything. There's so many homes in the air right now. The motion on this storm is sickening," storm chaser Spencer Basoco said.
The Oklahoman reported Norman Regional Medical Center spokeswoman Kelly Wells said the hospital's second floor was largely gone.
"All of our staff has been accounted for," she said. "None of our patients there have been critically injured. We're in the process of evacuating the hospital."
There were reports of gas leaks in Moore, with one destroyed home in flames.
Interstate 35 was shut down by the state highway patrol.
The Oklahoman reported the twister hit Moore about 3 p.m. and dissipated west of Lake Stanley Draper about 3:36 p.m.
The Warren Theatre was heavily damaged as well.
NBC News reported aerial footage showed widespread destruction.
"A large part of the community has been affected," Jayme Shelton, a spokesman for Moore, told MSNBC.
Oklahoma City police told NBC southern portions of the city and Moore sustained "major damage ... a lot of damage."
The National Weather Service had issued a tornado emergency for the Oklahoma City metro area earlier in the day, hours after a rash of twisters ripped through five states.
A twister was spotted in Newcastle, Okla., Monday afternoon, hours after tornadoes raced through Oklahoma, Kansas, Illinois, Iowa and Missouri, killing two people, injuring 21 and destroying dozens of homes, authorities said.
Tornadoes were reported Sunday and Monday, with baseball-size hail and other harsh conditions in the forecast, CNN reported.
The Oklahoma medical examiner identified two men killed by a twister that hit a trailer park in Pottawatomie County as Glen Irish, 79, and Billy Hutchinson, 76, both of Shawnee, The Oklahoman said.
At least 21 injuries were reported in Oklahoma and more in Missouri.
Dozen tornadoes were reported in Oklahoma, Kansas, Illinois and Iowa, the National Weather Service said.
Early Monday, a tornado touched down in Golden City in southwestern Missouri, and buzzed through two counties, Barton County Emergency Management Director Tom Ryan said.
More tornadoes were spotted in several locations in Iowa and in Carroll County, Ill., weather service officials said.
Fallin had declared a state of emergency for 16 counties. She said the declaration could be amended if necessary.
Emergency management officials reported dozens of homes were destroyed, The Oklahoman reported.
The Oklahoma Corporation Commission reported 23,000 utility customers were without power.
One tornado flipped three tractor-trailers and damaged four other vehicles at the Interstate 40-U.S. 177 overpass just west of Shawnee, sending several people to hospitals, officials said.
Truck driver David Bergquist said he was under the I-40 bridge near Shawnee as the tornado approached, comparing the scene to a popular 1996 movie about tornadoes and their power.
"What they did on 'Twister' was pretty damn accurate," he told The Oklahoman. "All I lost was a windshield."
Near Carney, Janee Keiser said she, her mother, her daughter and two granddaughters holed up in a cellar as a tornado wiped out their home.
"It's gone -- all the buildings, all the cars," Keiser said. "It took the garage, the barn, the shed -- it took it all.
"But we're all fine and that's the most important thing," she said. "The other stuff can be rebuilt."