"We've had a massive tornado, a huge one that has passed through this community," Oklahoma Governor Mary Fallin told a news conference shortly after the mid-afternoon storm, which struck near the end of the school day.
"We know there are a lot of injuries. We know we've lost a tremendous amount of structures throughout this community and throughout the state," she said, as the Moore police chief urged people to leave the area.
The dead included at least 20 children, most of them under the age of 12, according to Amy Elliott of the state medical examiner's office.
She later said she could not confirm a rise from an earlier official toll of 51 but that she had been told to prepare for 40 more bodies.
Live stream: Oklahoma tornadoes
CNN reported that at least 145 people had been hospitalised.
Reporters for local broadcaster KFOR-TV saw children as young as nine being pulled out of the Plaza Towers Elementary School in Moore, a residential community of 55,000 just south of Oklahoma City.
Anxious parents were being kept at a distance while search-and-rescue workers scrambled to free the students.
A second primary school, Briarwood, was also hit but did not appear to have suffered casualties.
From its news helicopter, KFOR's cameras captured scenes of widespread destruction, with street after street of single-storey homes in Moore stripped of their roofs and cars piled atop each other like toys.
Utility lines were down and gas lines exposed, triggering localised fires.
The Moore Medical Center was evacuated after it sustained damage, and state authorities called out the National Guard to help rescue efforts.
Obama ordered federal aid to supplement local recovery efforts.
On Twitter, the National Weather Service gave the tornado a preliminary rating of EF-4, indicating that it packed winds of 267km to 322 km per hour - more severe than a category five hurricane.
In downtown Oklahoma City, tornado sirens went off at least three times and the Interstate 35 highway - a busy north-south artery through the US heartland - was closed to all but emergency vehicles.
In Moore, live images from KFOR showed people wandering among the debris and even a couple of untethered horses from a local stable that somehow managed to survive the punishing storm.
"I had no idea it was coming," said a stable worker, who told how he survived the "unbearably loud" twister by taking cover in one of the stalls.
The tornado followed roughly the same track as a May 1999 twister that killed 44 people, injured hundreds more and destroyed thousands of homes.
Tornadoes frequently touch down on Oklahoma's wide open plains, but Monday's twister struck a populated urban area and raised fears of a high casualty toll.
Because of the hard ground, few homes are built with basements or storm shelters in which residents can take cover.
Oklahoma City lies inside the so-called "Tornado Alley" stretching from South Dakota to central Texas, an area particularly vulnerable to tornadoes.
But Moore's residents were shocked at the sprawling moon-like landscape left behind by the massive twister.
"There's nothing left of my house," an unidentified woman told CNN.
"The front is still standing but the back is gone. My bathroom honestly is untouched. We've lost animals. We've lost everything," she said.
Some 35,000 people remained without power early on Tuesday, according to OG&E, the local utility.
On Sunday, a powerful storm system churning through the US Midwest spawned tornadoes in Iowa, Kansas and Oklahoma, destroying homes and killing at least two people, US media reported.
- AAP
