Thousands of flights have been cancelled in airports in central and eastern states and further disruption is expected on Wednesday.
Tens of thousands of homes are without power and the National Weather Service has advised against travel.
Even usually resilient Chicago has said schools would close on Wednesday.
The city is expected to be hit by up to 24in (60cm) of snow, prompting authorities to call Chicago's first "snow day" for public schools in 12 years.
The National Weather Service (NWS) said the storm would hit the mid-Atlantic or north-east coast late on Wednesday before heading to Nova Scotia in Canada's maritime provinces.
"The storm has produced blizzard conditions with snow and blowing snow across the Central Plains. Total snowfall accumulations of one to two feet of snow are expected for a large swath of the central and north-eastern states," the NWS advised.
Heavy freezing rain was expected south and east of the snow area, the service said.
Ribbons of ice
Most of the airlines using Chicago's O'Hare airport - one of the busiest in the world - stopped their services Tuesday afternoon as the storm set in.
The airport said it expected limited or no operations on Wednesday.
The storm has turned roads into ribbons of ice, stretching the resources of emergency responders to rescue stranded motorists. Illinois state police said much of the state's road system was impassable.
In Missouri, where more than a foot (30cm) of snow had fallen by midday Tuesday, authorities closed the state's entire 250-mile stretch of Interstate 70 between St Louis and Kansas City.
Meteorologist Jeff Johnson of the National Weather Service in Iowa told Associated Press news agency the storm was sure to "cripple transportation for a couple of days".
Oklahoma City and Tulsa, Oklahoma, were paralysed as the storm reduced visibility on the roads and snow drifts piled in drifts as high as 4ft.
The Tulsa World newspaper announced that it would be unable to publish on Wednesday for the first time in its 105-year history.
Superbowl on
The series of storms that has hit the US this winter is also wreaking havoc with government budgets. Clean-up costs are placing pressure on already tight public funds.
But other businesses are benefiting, with concerned residents stocking up on essentials.
"Milk, bread, toilet paper, beer," Todd Vasel, who works at the St Louis-based grocery chain Dierbergs, told AP. "It's been the equivalent of Christmas Eve, which is normally one of our biggest days of the year."
Hardware stores in affected regions have reported selling out of snow shovels, ice-melting salt and generators.
However, plans continued in Dallas, Texas, for Sunday's Super Bowl between the Green Bay Packers and the Pittsburgh Steelers - two teams accustomed to playing US football in adverse wintry conditions.
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