Blizzard conditions are likely from portions of Long Island, N.Y., to northeastern Maine, New Brunswick and western Nova Scotia, AccuWeather said.
The storm is forecast to explode off the New England coast and could be the most powerful non-hurricane to affect the Northeast in the past 30 years, according to Earth Networks meteorologist Anthony Sagliani.
"Our biggest concern is the potential for damaging wind gusts especially near the southeast New England coast," the weather service in Boston said. "Power outage risk followed by arctic air Fri/Sat a big concern!"
A freeze watch was in effect Tuesday night for Lake City, Fla., 60 miles west of Jacksonville. A wintry mix was forecast for Wednesday. The snow, wind and travel disruptions will roll north Wednesday night through Thursday night.
In all, some 208 million Americans are forecast to wake up to freezing temperatures Wednesday morning, weather.us meteorologist Ryan Maue said.
And the cold isn't going away.
"After a brief moderation from the cold at midweek, more bitter cold and downright harsh air will return," AccuWeather meteorologist Kyle Elliott said.
The next air mass will be up to 10 degrees colder than the front that froze the Northeast the last few days, Elliott said.
Some all-time cold temperature records could be set.
"I don't know if we are going to set any records for heating energy usage, but we are certainly going to stress-test the system, " said former weather service meteorologist Gary Szatkowski.
The extended cold wave, which began creeping across the nation before Christmas, enveloped a swath of the country from Montana and Texas to the East Coast. The Southeast wasn't spared — Atlanta awoke to 13 degrees on Tuesday and barely broke above freezing later in the day.
The weather already has been deadly. In Wisconsin, the Milwaukee County Medical Examiner's Office said the bodies of two men found outdoors Sunday showed signs of hypothermia. In Bismarck, N.D., police said cold weather "may have been a factor" in the death of a 52-year-old man whose body was found lying in the snow.
In Indiana, the 30,000 students in the Indianapolis school system were kept home because of "dangerous weather conditions." The temperature at 7 a.m. was -11 degrees with a wind chill mark below -20 degrees.
Cincinnati's 35,000 students had their holiday break extended at least a day when authorities closed the schools because of the cold. Other districts in Ohio, including Canton, shut schools for the day.
In western New York, blinding snow Tuesday led to a massive pileup on I-90 near Buffalo, which involved at least 75 cars.
Boston schools soldiered on, but some nearby districts such as Everett, Mass., shut down for the day; others delayed opening a couple hours. On Saturday, Boston could challenge its lowest maximum temperature ever recorded for the date — 7 degrees, in 1896, AccuWeather said.
In South Dakota, Aberdeen hit -32 degrees on New Year's Day, smashing a record that stood for 99 years. In Nebraska, Omaha's 15-below 0 degrees on Sunday broke a record dating to 1884.
New York Mayor Bill de Blasio kicked off his second term Monday with an outdoor swearing-in ceremony and temperatures in the teens. It may not get that warm on Saturday.
— The Associated Press contributed to this report.