The system, which dumped heavy rain and snow over the region on Tuesday, has already caused some flight delays.
Forecasters say more than 1 ft of snow could fall in western Pennsylvania, western New York and Vermont before Thursday.
More than 43 million Americans are expected to travel during the holiday.
The storm is also threatening to ground the giant balloons at the Macy’s Thanksgiving Day Parade in New York.
City regulations bar the inflatables from being used when sustained winds exceed 23 mph or when gusts top 34 mph.
The balloons of beloved characters such as Mickey Mouse and the Pillsbury Doughboy are due to be made ready on Wednesday evening.
New York Governor Andrew Cuomo has issued a winter weather warning, urging motorists to use extreme caution.
Meteorologists also predict the storm could bring 2-4 in of rain up the Atlantic coast from Richmond, Virginia, to Portland, Maine.
“It couldn’t have come at a worse time,” said meteorologist Tim Morrin, of the National Weather Service.
“Visibility will be restricted not only by the rain and wash from other cars, but from the fog.”
Late on Tuesday, flight delays were reported in Charlotte, North Carolina; Philadelphia, Pennsylvania; Memphis, Tennessee; and Baltimore, Maryland.
Daniel Baker, of flight-tracking service FlightAware, said that most airlines expect to continue operating full schedules, although further delays were likely.
Some travelers were getting on earlier flights to avoid ending up stranded.
Lisa Jablon was originally due to fly on Wednesday morning from New York City to Syracuse, New York state, but she moved her flight to Tuesday night.
“I’m flying up to spend the holiday with my boyfriend’s family and I didn’t want to get stuck,” she told the Associated Press news agency.
The icy weather started in the western states and has caused at least 10 fatal road crashes.
Deaths from weather-related accidents were reported in Oklahoma, Texas, New Mexico and California.
Thanksgiving Day celebrates the harvest and blessings of the past year.
It has been marked for hundreds of years, and is generally thought to commemorate a 1621 harvest feast the US Pilgrims shared with Indians after settling at Plymouth, in what is now Massachusetts.
The modern festival sees millions of people travel to be with family, eat turkey feasts, watch NFL football matches and – in recent years – plan or even begin their assault on the holiday sales.
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