0553 GMT April 23, 2019
Forecasters say temperatures over the next few days will go as low as -30C in the Midwest, with wind chill making it feel even colder, BBC reported.
At least five people are reported to have been killed across several states as a direct result of the cold weather.
Snow is expected to fall as far south as Alabama and Georgia.
As much as 24in (60cm) of snow is forecast in the state of Wisconsin, and 6in in Illinois.
Snow is expected to fall throughout Wednesday, from the Great Lakes region into New England.
A state of emergency has been declared in the Midwestern states of Wisconsin, Michigan and Illinois, as well as in the normally more clement southern states of Alabama and Mississippi.
"This could possibly be history-making," said Ricky Castro, a National Weather Service (NWS) meteorologist in Romeoville, Illinois.
As of Tuesday, multiple deaths have been confirmed, including a man killed by a snow plough in Chicago; another found frozen to death in a Milwaukee garage; and a young couple died after a traffic accident in snowy conditions in northern Indiana.
Impacts on daily life
Hundreds of schools have been closed in the affected states, and hundreds of flights grounded.
The US Postal Service has also cancelled mail deliveries to the region on Wednesday. Even beer deliveries in Wisconsin have been hit by the cold, with Wisconsin-based companies delaying shipments over fears the beer would freeze within the trucks.
The NWS is warning that frostbite is possible within just 10 minutes of being outside in such extreme temperatures.
Residents of the city of Chicago in Illinois, long used to freezing winters, have been warned to expect an unusually deep and dangerous period of cold.
Chicago mayor Rahm Emanuel has urged people not to venture outdoors unless they have to, and the city has set up dozens of "warming centers" for the estimated 80,000 rough sleepers there.
Chicago police say people are being robbed at gunpoint of their coats. Those wearing Canada Goose jackets, which can cost as much as £900 ($1,100), have been targeted, local media report.
Weather officials in the state of Iowa have warned people to "avoid taking deep breaths, and to minimize talking" if they go outside.
Landmarks including the Lincoln Park Zoo, Field Museum and Art Institute are closed.
Chicagoans out in the cold on Wednesday will also be hard pressed to find a cup of coffee - La Colombe is closing all five of its Chicago cafes, as are other local shops.
Delivery pizza – a traditional bad-weather food in the US – has also been affected, with Chicago's famous deep dish pizza chain Lou Malnatis and other regional restaurants closing early on Tuesday and Wednesday.
Animal rights organization Peta has warned people to bring animals indoors.
Farmers across the Midwest have been taking measures to protect their livestock, including building igloos for chickens.
In North Dakota, cattle ranchers Joey Myers and Scott Bailey told Reuters they planned on staying up with their animals during the cold snap to prevent fatalities.
Frigid weather could cause pregnant cows to deliver ahead of schedule, the farmers said, and newborn calves cannot survive such frigid conditions.
Meanwhile, police in McLean, Illinois, some 150 miles (240km) from Chicago, poked fun at the impending freeze, announcing that Elsa, from Disney's Frozen, has been arrested over the extreme cold.
What is causing this?
The bitterly cold conditions are the result of a spinning pool of cold air known as the polar vortex.
It normally circles the stratosphere over the North Pole, but its current has been disrupted and it is now moving south into the US.
Forecasters are attributing this to a sudden warming above the North Pole, caused by a blast of hot air from Morocco last month.
This weather system split the polar vortex and caused it to drift south, Judah Cohen, a winter storm expert for Atmospheric Environmental Research, told AP.