Airlines reported weather-related delays and cancellations, with major airports in Chicago, Washington, New York City and Newark, New Jersey, scrubbing dozens of flights, according to the Federal Aviation Administration and FlightStats.com.
The fast-moving snowstorm stretched from Missouri to Maine, as a steady rain fell in the southeastern states.
The storm will "produce a pretty good swath of snow over about a 24-hour period," said Brian Korty, a meteorologist with the National Weather Service.
The heaviest accumulation was expected in central Pennsylvania, New York state and interior New England, which could see between 4 and 8 inches of snow. Mountainous areas and parts of eastern Maine could be walloped by a foot of snow.
More than 110 million people across the Midwest and along the East Coast will be affected, said AccuWeather meteorologist Alex Sosnowski.
"Snow will fall on and impact every major city and rural area from St. Louis to Boston, including Chicago, Detroit,Cincinnati, Cleveland, Pittsburgh, Philadelphia and New York City," he said.
By midday on Saturday, areas of north-central Illinois reported 7 inches of snow over the past 24 hours, while the town of Warsaw, New York, near Lake Ontario, reported 21 inches, according to the National Weather Service.
Snow started falling early in Philadelphia, New York, and Boston, with the heaviest accumulations expected through the evening and overnight hours, forecasters said. Up to six inches of accumulation was expected in major cities on the East Coast, forecasters said.
The same region was slammed a week ago by another massive storm system that left parts of the Mid-Atlantic and East Coast shoveling out from a half-foot of snow.
Utility companies across the region put extra crews on duty and made preparations for possible outages.
New York City's Sanitation Department for a second Saturday issued a snow alert and was readying its fleet of some 365 salt spreaders, 282 front-end snow loaders and 1,800 plows.
The driving snow was a sobering reality check for an expected 35,000 pub crawlers dressed like Santa Claus, who came to New York for the annual SantaCon. The revelers wore Santa suits or red minidresses with white trim and nearly all had Kris Kringle hats topped with a white pom-pom.
The precipitation and freezing temperatures made roads and highways treacherous for drivers. Michigan State Police said they had handled 20 crashes since midnight, including one fatal accident.
The snowstorm comes on one of the busiest shopping weekends of the year during one of the shortest holiday buying seasons with only four weeks separating Thanksgiving and Christmas.
At a shopping mall north of Philadelphia, schoolteacher Amanda Nixon, 30, arrived early with her 9-year-old daughter hoping to get errands done before the snow picked up later in the day.
"We like the snow," she said, "We just don't like to drive in it."
Nixon said she thought other shoppers would put off holiday gift buying because of the second weekend of bad weather.
"I think a lot of people are nervous that this is going to be another big one," she said.
AccuWeather said the system was expected to move out of the area by Sunday, but slushy conditions could turn icy in frigid evening temperatures.
(Additional reporting by Dave Warner in Philadelphia. Editing by Barbara Goldberg, Vicki Allen and Gunna Dickson)