Blizzard conditions across the Dakotas, Minnesota and Wisconsin have forced many schools and businesses to close.
Nearly 6,000 US flights were delayed or cancelled on Wednesday.
While about 75 million people in 29 states are under winter weather alerts, parts of the eastern US are forecast to experience record high temperatures.
Wind gusts potentially reaching 50mph (80kph) and a wind chill as low as -50F (-45C) in some parts are predicted.
In northern states, forecasts of up to two feet (0.6m) of snow in some parts could mean areas endure their biggest snowfalls for 30 years.
Minnesota's governor Tim Walz said the National Guard will be available to help motorists who become stuck in the blizzard conditions there.
"This is a reminder to stay home and limit travel if possible," the Utah Department of Transport warned morning commuters.
Forecasters said the storm system could produce an icy band across 1,300m (2,100km) from Nebraska to New Hampshire.
Meanwhile, typically sunny and warm Los Angeles, California, will see major snow and winds up to 75mph in the mountains and foothills of Ventura and Los Angeles County.
All of California "will be able to see snow from some vantage point later this week," tweeted David Swain, a climate scientist at the University of California-Los Angeles.
Unlike the western part of the country, parts of the eastern US will see record highs - Washington DC could hit 80F on Thursday, which would break a record set in 1874.
Orlando, Florida, temperatures could hit 90F and in Louisiana, New Orleans could reach 84F.
"All winter, we've seen this persistent pattern, where the western US is seeing below-average temperatures and the eastern US is seeing above-average temperatures," climate scientist Andrew Kruczkiewicz, a researcher at Columbia University, told BBC News.
Large parts of the country are under weather alerts, including Toronto, which is expecting 4-10in (10-15cm) of snow, ice pellets and possible freezing rain.
Though the country just had record-breaking warm temperatures for February, parts of Toronto could see significant ice build-up.
Parts of Alberta and the prairies are facing extreme cold warnings, with temperatures dropping in some regions into the -40F (-40C) range with wind chill.