A winter storm has already blanketed areas of Canada and the north-eastern US with up to 2ft of snow.
It has been blamed for 16 deaths and the cancellation of more than 5,000 flights since Wednesday.
Forecasters say temperatures in the Midwest could feel as low as -58F (-50C) with the effect of wind chill.
Authorities have warned residents to remain indoors, both for their own safety and to keep roads clear for snow removal.
In Canada, tens of thousands of people on the island of Newfoundland remain without power due to a transformer fire linked to heavy snow.
“The coldest weather in years will be making its presence known from the Upper Midwest to the Mid-Atlantic region,” the US National Weather Service said in statement.
The states of Ohio, South Dakota and Illinois are among those set to be hit.
The weather service said “an incredibly strong surge of bitterly cold Arctic air” would sweep across the country from Saturday night until Tuesday.
It is set to continue to the north-east, where residents are still digging out from the week’s deadly snowstorm.
It could bring some of the coldest temperatures in two decades.
“The last really big Arctic outbreak was 1994,” Reuters news agency quoted Bob Oravec, a forecaster with the National Weather Service, as saying.
“Outbreaks like this don’t occur everyday.”
In Canada, the temperature dropped as low as -29C (-20F) in Toronto and -38C in Quebec City with wind chill on Thursday – the lowest seen in at least two decades there.
Heavy snow has also affected states including New York, Connecticut and Massachusetts, with school closed, transport systems drawn to a halt and residents told to stay at home.
Boston was said to be the worst hit with nearly 18in of snow.
Sixteen deaths have been blamed on the wide-ranging storm, according to the Associated Press news agency.
A salt storage worker was killed in Philadelphia when a 100-ft pile of road salt fell and crushed him. A woman suffering from Alzheimer’s disease in New York state froze to death after she wandered away from her rural home.
Some 1,200 flights were cancelled across the US and about 6,000 flights delayed on Saturday, according to reports. This followed more than 4,000 cancellations earlier in the week.
Chicago’s O’Hare International Airport and Newark Liberty International Airport in New Jersey were said to be among the worst affected.
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