Worst hit was Moore, south of Oklahoma City, where neighborhoods were flattened and schools were destroyed by winds of up to 200mph.
About 120 people, including 70 children, are being treated in hospitals for their injuries.
Search and rescue efforts are continuing throughout the night.
Monday’s twister hit Moore, a suburb of about 55,000 people, and remained on the ground for about 45 minutes.
The Oklahoma chief medical examiner’s office said children were among the 51 dead.
At least two schools were devastated by the high winds, and there are reports that children are still unaccounted for.
Oklahoma Governor Mary Fallin said it was a “tragic” day, and that President Barack Obama had called her to offer assistance.
More than 200 Oklahoma National Guardsmen as well as out-of-state personnel have been called in to assist the search-and-rescue effort.
Shocked survivors spoke of the tornado’s power.
“We locked the cellar door once we saw it coming, it got louder and next thing you know is you see the latch coming undone,” survivor Ricky Stover said.
“We couldn’t reach for it and it ripped open the door and just glass and debris started slamming on us and we thought we were dead, to be honest.”
Melissa Newton said: “There’s shingles and pieces of sheet rock and wood in our yard and all across our neighborhood. Some homes are completely gone. It’s devastating.”
James Rushing said he had rushed to the Plaza Towers Elementary School, where his foster son Aiden was a pupil, to see it destroyed by the storm.
“About two minutes after I got there, the school started coming apart,” he told the Associated Press news agency.
The National Weather Service (NWS) said Monday’s tornado had generated winds of up to 200 mph.
“It’s certainly the most powerful tornado that I’ve ever dealt with in my 20 years with the weather service,” said NWS meteorologist Rick Smith in Norman, Oklahoma.
The town of Moore was hit by a severe tornado in May 1999, which had the highest winds ever recorded on Earth.
But Betsy Randolph of the Oklahoma Highway Patrol told local news station Skynews 9 that the damage on Monday appeared to exceed that of the last devastating tornado.
Tornadoes, hail and high winds also hit Iowa and Kansas, part of a storm system stretching from Texas to Minnesota.
On Sunday, a tornado smashed a trailer park on Highway 102 near Shawnee, Oklahoma. Oklahoma’s state medical examiner confirmed on Monday that two people had been killed in the area.
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