Entire neighbourhoods were flattened within seconds as the twisters, triggered by a "very dangerous" and fast-moving weather system, touched down in as many as 10 states.
Forecasters said the extreme weather - which destroyed homes, uprooted trees and flipped cars upside down - could affect more than 50 million people.
According to the National Weather Service, more than 60 tornadoes struck, unleashing 80mph winds and hail stones up to two inches in diameter.
Illinois was struck the hardest. At least six were killed and dozens more injured, but with communications difficult and many roads impassable, it remained unclear how many people might be hurt.
At one hospital in Peoria, Illinois, doctors were treating at least 24 casualties, some of whom had head injuries and broken bones.
Indiana, Iowa, Missouri, Kentucky, Ohio, Michigan and Wisconsin were buffered by the storm, which weakened as it tracked east towards Pennsylvania, New York, Maryland and New Jersey.
Washington, a town of 16,000 in Illinois, appeared to have the most severe damage.
"I ran into the basement, jumped onto my wife and daughter and looked up and just saw white above us," said Ryan Bowers, a Washington resident whose house was destroyed.
"It was amazing."
Anthony Khoury, who saw a twister rip through Washington, told Sky News: "Most of my neighbourhood is completely destroyed, everything has been demolished.
"Families have lost their homes, people don't have anywhere to sleep and the electricity has gone."
Jeff Leeman, who was in his backyard with his son when a tornado struck Pekin, Illnois, added: "In a matter of seconds ... it was right on top of us.
"We hustled in the house and before we knew it, it was gone. It was that fast."
Two people, an 80-year-old man and his 78-year-old sister, were killed in Washington County; three were killed in Massac County, near the Kentucky border; and the sixth victim was reported in Tazewell County.
Ryan Allan Rickman of Leslie, Michigan, died when his vehicle was crushed by a fallen tree.
The tornadoes brought down phone lines, caused thousands of power failures and left debris strewn across roads.
The severe weather also caused the cancellation of many flights, while the Baltimore Ravens' game against the Chicago Bears at Soldier Field was temporarily suspended in the first quarter due to lightning in the area.
Meteorologist Matt Friedlein said such powerful storms rarely occur so late in the year because the climate is usually too cold.
However, temperatures had been forecast to climb to as high as 26C (78F), he said, which is warm enough to produce severe weather when coupled with strong winter winds.
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