"This is not like a snow day when you were a kid," President Joe Biden told reporters at a White House briefing on the weather and transport turmoil.
"This is serious stuff," he added, urging people to heed warnings from local authorities.
Blinding whiteouts and hazardous road conditions were already being seen in parts of the country slammed by a dangerous Arctic front.
AccuWeather forecasters have said the storm could rapidly strengthen into what is known as a "bomb cyclone" through a process known as "bombogenesis," when the barometric pressure drops and a cold air mass collides with a warm air mass.
National Weather Service (NWS) forecaster Michael Charnick tweeted a video showing drivers struggling along a highway between Colorado and Wyoming, where the temperature with wind chills plummeted to -40 degrees Centigrade.
The U.S. National Weather Service released key safety messages on its Twitter account, warning snow squalls -- bursts of moderate to heavy snow lasting an hour or two -- had already happened or were expected from the Central Plains to the mid-Atlantic and Northeast.
"People exposed to extreme cold are susceptible to frostbite in a matter of minutes," the agency cautioned.
"Areas most prone to frostbite are uncovered skin and the extremities, such as hands and feet. Hypothermia is another threat during extreme cold."
Blizzard conditions stranded 100 motorists in Rapid City and Wall in South Dakota, the Pennington County Sheriff's Office tweeted.
"NO TRAVEL advised," the sheriff's office added.
In Minneapolis and Saint Paul, more than eight inches (20.3 centimeters) of snow accumulated over a 24-hour period, the NWS said in a Thursday morning update.
In Buffalo, New York, forecasters called it a "once-in-a-generation storm" with wind gusts of more than 65 miles per hour (105 kilometers per hour), wind chills as low as 10 to 20 degrees F below zero, and power outages.
The storm comes as the Transportation Security Administration said it expects holiday travel volume to be close to pre-pandemic levels, with the busiest day on Thursday, three days before Christmas.
The majority of US flight cancellations have so far been at Chicago O'Hare or Denver, both international hubs.
American Airlines, Southwest Airlines and United Airlines had already taken steps to issue weather waivers to allow passengers to change their flights without fees.
The American Automobile Association estimated that more than 112 million people will travel 50 miles or more from home between Friday and January 2, the vast majority of them -- 102 million -- by car.
And in some parts of the United States, those cars will be going nowhere.