Flights headed for New York, Philadelphia and Newark, New Jersey, were experiencing delays of more than an hour due to the inclement weather, the Federal Aviation Administration said.
Nearly 900 US flights had been cancelled on Wednesday (local time), according to FlightAware.com.
The National Weather Service issued blizzard and winter storm warnings in Illinois, Indiana and Ohio, as well as much of the Northeast, and warned that the wintry weather would make for "treacherous" driving conditions for holiday travelers.
More than six inches of snow might fall in those regions, while the area from western New York up into central Maine could get from 12 to 18 inches, the NWS said.
As of Wednesday morning, Bloomington, Indiana, already had nearly a foot of snow and Indianapolis had about seven inches, according to AccuWeather.com.
Severe thunderstorms and widespread rain were expected from southeast Virginia to Florida, with the eastern counties in North Carolina and South Carolina under tornado watches or warnings, the NWS said.
The wet and snowy conditions follow a major winter storm system that swept through the southern United States on Tuesday, spawning tornadoes in several states and causing the deaths of at least two people in weather-related road accidents.
Twisters struck in Alabama, Mississippi, Texas and Louisiana, flattening houses and causing injuries, according to the weather service.
Declaring a state of emergency, Mississippi Governor Phil Bryant deployed resources to the multiple counties in that state that reported damaged homes and businesses, power outages and flooding.
Tuesday's storms also contributed to a 21-vehicle pile-up that shut Interstate 40 in downtown Oklahoma City and caused power outages for tens of thousands of residents.
A Texas man died after an accident involving a toppled tree in the road, and there was another weather-related fatality on I-44 in Oklahoma, according to local authorities.
In the US southeast, nearly 200,000 homes and businesses remained without electricity on Wednesday following a Christmas Day winter storm packing snow, high winds and tornadoes.
The storm dumped record snowfalls in North Texas and Arkansas.
About 1,000 people spent the night on cots at the Dallas/Fort Worth International Airport after some 400 flights were canceled there on Tuesday due to weather, said Cynthia Vega, media relations manager at the airport.
On Wednesday morning, about 50 more flights were canceled, she said.
"We're hoping to get passengers back on track," Vega said. "It's probably going to be a little hectic at the airport."
(Reporting by Colleen Jenkins; Additional reporting by Corrie MacLaggan; Editing by Paul Thomasch and Gunna Dickson)