"It's going to be brutal," Weather Channel coordinating meteorologist Tom Moore said of the expected sub-zero temperatures. "People that are vulnerable are really going to be hurting."
While the immediate focus was on snow — with up to 10 inches possible in New York City, possibly 18 inches burying New England, and more than 1,800 flights canceled — the cold behind the snowstorm could be crippling.
The high temperature in New York City will be in the teens on Friday during the day and drop to between 5 and 8 degrees in the evening, with the wind chill making it feel well below zero. Lows in Boston will be below zero. Maine could see the mercury drop to minus 30 after dark.
"That is a very, very dangerous set of circumstances," Massachusetts Gov. Deval Patrick said. He dismissed all state workers at 3 p.m. and urged residents to minimize time outside and be aware of frostbite and hypothermia symptoms.
“I think I’m more concerned about the terrible cold Friday night rather than the storm itself," David Ball of Scituate, Mass., which was facing coastal flooding, told NBC affiliate WHDH. "Hopefully the power stays on."
A second wave of icy weather will hit the nation's midsection by late Sunday, stretching from the upper Midwest to Kentucky and Tennessee, forecasters said.
Chicago will struggle to get above minus 8 and by Monday morning the wind will make it feel like it's 40 below zero there.
In Green Bay, Wis., where the Packers host an NFL playoff game Sunday evening, the low temperature could reach minus 18.
"Even Atlanta's northern suburbs could be in single digits by Monday night," Moore said.
Larry Wittmers, a hypothermia expert at the University of Minnesota-Duluth medical school, said it's not necessarily the coldest areas that face the most peril.
"True hypothermia cases turn up more often in more southern regions because people are not prepared and don't know what to do," Wittmers said.
How long people can safely spend outside depends on how wet or windy it is and how they are dressed, Wittmer said. Shoveling snow or other exercise can be dangerous because sweat reduces the insulation capability of clothing, and consuming alcohol can speed heat loss and reduce awareness of the cold.
And even though record snowfall is not expected, the cold could make roads even more hazardous because the snow-melting salt that homeowners and road crews use loses effectiveness at between 10 and 20 degrees.
To give plows time to work and guard against vehicles getting stranded, New York's Gov. Andrew Cuomo declared a state of emergency and closed several major roads, including the Nassau and Suffolk county sections of the Long Island Expressway from midnight to 5 a.m.
At the Pine Street Inn shelter in Boston, vice president Heidi Daniels was preparing for a packed house.
"We won't turn anybody away," she said. "We'll pull out cots and mats and make sure everybody has a warm place to stay tonight."
Winter storm warnings and advisories were in effect in 22 states, stretched from Chicago through the New York tri-state region into New England and affecting an area home to more than 90 million people.
Flights were being canceled by the hundred at some of the nation's busiest airports. Five hundred had been scrapped at Newark, LaGuardia and Kennedy; Boston's last departure was slated for 8:30 p.m.; almost 600 were off the boards at Chicago's O'Hare, according to FlightAware.
Snow began to fall in Boston, the first major city on the East Coast to be hit, at around 1:30 a.m. ET on Thursday.
"It's going to be a long-duration event," said Michael Palmer, lead meteorologist at The Weather Channel. "The wind is going to whip around the snow and reduce the visibility, creating near-blizzard conditions in Boston, much of Connecticut and then down maybe as far south as New Jersey and even New York City."
The National Weather Service issued a blizzard warning on Long Island in New York beginning at 6 p.m. Thursday, predicting inch-an-hour snow with 45 mph winds during the worst of it Thursday night. Blizzard conditions also are warned for Cape Cod and coastal Massachusetts.
Gov. Patrick said that storm models were showing heavy bands that could sock some communities with up to 2 feet of snow, depending on wind drifts, while the rest of the state was anticipating 8 to 10 inches.
In New York City, the administration of newly minted Mayor Bill DeBlasio said it would do its best to keep outdoor subway, Long Island Rail Road and Metro-North trains moving, calling out the Metropolitan Transportation Authority's ice-busting equipment.
Boston Mayor Tom Menino — in his last official act in office — pre-emptively declared a snow emergency for Thursday and closed the city's schools Friday as weather models pointed to up to 18 inches of new snow.
Buffalo was also predicted to get a 12- to 18-inch wallop, and accumulations of 8 to 12 inches were expected in areas of Vermont, New Hampshire and Maine.
NBC News' Ron Mott contributed to this story.