According to the National Weather Service, the preliminary rating of the Newcastle-Moore tornado was at least EF-4, the second most powerful type of twister.
More than 120 people were injured. At least 10 people were in critical condition.
President Obama has declared a major disaster in Oklahoma. The action makes federal funding available to people in counties of Oklahoma, Cleveland, Lincoln, McClain, and Pottawatomie.
Two chief officers with the Los Angeles Fire Department will be leaving for Oklahoma early Tuesday morning to join FEMA's national response command staff.
Rescue crews are searching through debris for survivors. Plaza Towers Elementary School took a direct hit, leveling much of the campus. Witnesses say there were 75 people in the school -- many of them third graders -- when the tornado hit. They were sheltering in the hallway, which was their designated safe zone.
The building sustained extensive damage, according to Gary Knight of the Oklahoma City Police Department. Children were seen being pulled alive from the rubble of Plaza Towers Elementary School.
Briarwood Elementary School was also hit by the tornado. Officials say all children there have been accounted for.
The massive tornado stretched more than a mile wide, destroying much of the town of Moore, a community of about 56,300 people located just south of Oklahoma City. Homes were shattered, others were on fire and everything in the twister's path was torn apart.
Moore was hard hit by a monster of a tornado in 1999. That storm had the highest winds ever recorded near the Earth's surface. Forty-two people died.
Oklahoma Emergency Management tells ABC News that the National Guard has been activated and is being sent to the Moore area to assist with disaster response.
More than 50 tornados slammed six states in two days. Several tornadoes ripped through the nation's mid-section Sunday leaving a deadly trail of destruction. Oklahoma and Kansas were hit the hardest and dealt with the brunt of the blows.
A 79-year-old man, later identified as Glen Irish, was killed Sunday when a tornado tore through a mobile home park in the town of Shawnee, located 35 miles southeast of Oklahoma City.
The Office of the Oklahoma Chief Medical Examiner said the twister, nearly a mile wide, also claimed the life of a second 76-year-old man. He was found dead in his car.
Emergency officials said 39 people were injured throughout Oklahoma, and up to 35 homes were significantly damaged. Two highways were shut down in the area.
"Everything was just gone, I mean, you see like beds in the yard," said John Welsh, a KFOR-TV helicopter pilot. "Like you took the house, you put it in a gigantic blender, you turned it on pulse for a couple minutes and then you just dumped it out."
May is the most active month for tornadoes. Travelers heading toward the Midwest were urged to check on their flights. Many delays are being reported to flights in and out of the airports in the Midwest area.
The Associated Press contributed to this report.