More than 90 million people around the country are expecting hazardous weather on Thursday into Friday morning.
Thirty-seven states are under winter weather alerts for heavy snow, ice, brutal cold and wind Thursday night.
More than 2,100 U.S. flights on Thursday have been canceled as of 9 p.m. ET, with airports in Nashville, Tennessee; Denver; and Chicago the most impacted, according to FlightAware. Over 1,900 flights on Friday have also been canceled, with airports in New York, Denver and Newark, New Jersey, among the most impacted.
There were numerous accidents around the country Thursday, with some interstates closed from Oregon to Michigan as the wild weather moved across the country.
Police in Nashville are investigating a multi-car collision on Interstate 40 that blocked off all the westbound lanes, according to WKRN.
New York Gov. Kathy Hochul issued a winter storm advisory and advised people to avoid any unnecessary travel in several parts of the state. Two weather systems are expected to produce snow and gusting winds, resulting in snow, ice-covered roads and low visibility, according to a statement from her office.
"Areas in Western New York and the North Country are already experiencing lake effect snow and we're anticipating up to six inches of snow in Downstate regions between tonight and tomorrow morning," Hochul said in a statement.
A winter storm is headed for the Interstate 95 corridor, where earlier this week, weather conditions left people trapped on the highway for more than 24 hours in Virginia.
The I-95 corridor is expected to see 3 to 6 inches of snow, with localized amounts of up to 8 inches in Massachusetts and Maine.
Virginia state officials and agencies are strongly cautioning drivers to stay off the roads due to the wintry conditions.
Virginia Gov. Ralph Northam declared a state of emergency on Wednesday due to the winter weather.
Kentucky Gov. Andy Beshear also declared a state of emergency Thursday, amid heavy snowfall across the state.
"We are urging Kentuckians to stay off the roads if possible," Beshear said in a statement. "The weather we are continuing to see across Kentucky is dangerous."
More than half a foot of snow is possible in Tennessee, Kentucky and West Virginia.
Dozens of schools announced they will be closed on Thursday due to weather conditions, according to Memphis ABC affiliate WATN.
The storm system is moving out of the central Plains and the Mid-South and will form into a coastal low, bringing a widespread snow event from Nashville to Washington. D.C., Philadelphia, New York City and Boston.
A winter storm warning is in place for Boston and Nashville and a winter weather advisory is in place for Washington. D.C., Philadelphia and New York City.
Nashville could see several inches of snow.
Areas, including New York City, Boston and Philadelphia, are expected to get the first significant snow of the season.
Snow begins in D.C. Thursday evening and will continue overnight. Snow starts in Philadelphia after midnight and in New York City after 2 a.m. and into the Friday morning commute. Snow in Boston will begin before the morning commute and continue into the afternoon.
Behind the eastern snowstorm, an arctic outbreak is moving in with wind chills as low as minus 60 degrees in the northern Plains.
Brutal cold continues to spread from Montana to Illinois where wind chill alerts are in effect.
Near-zero wind chills are expected for Friday morning in Nashville and in the teens from Dallas to Birmingham, Alabama, and Atlanta.
ABC News' Mina Kaji contributed to this report.