Flash flooding is possible overnight Tuesday into Wednesday on the East Coast.
Americans are bracing for a cross-country storm during Thanksgiving week, one of the busiest holiday travel weeks of the year.
The storm -- which dumped rain and snow in the West this weekend -- is now marching east, bringing damaging winds and potential hail and tornadoes to the South.
Jackson, Mississippi; Rolling Fork, Mississippi; and Alexandria, Louisiana, are most likely to get hit by the severe weather Monday afternoon and evening. New Orleans and Mobile, Alabama, will be in the bull's-eye overnight and Tuesday morning.
On Tuesday, the storm will gain speed as it barrels into the Northeast. Those driving along the Interstate 95 corridor to reach their Thanksgiving destinations should exercise extreme caution.
Rain will reach the Washington, D.C., Maryland and Virginia area by the morning rush hour and will last all day.
By Tuesday evening, the heaviest rain is expected from the Carolinas to New York City. Flash flooding is possible overnight Tuesday into Wednesday.
By Wednesday morning, the heavy rain will be slamming Boston.
Snow will begin in northern New England Tuesday afternoon and continue through Wednesday night. Six to 12 inches of snow is forecast for parts of Massachusetts, Vermont, New Hampshire and Maine.
Behind this cross-country storm will be the first bitter cold of the season.
Temperatures on Thanksgiving morning will feel like the 20s and 30s for the majority of the U.S.
The Federal Aviation Administration forecasts Wednesday to be the peak day for flights, with more than 49,000 commercial and general aviation planes in the skies.
FAA Administrator Michael Whitaker said his agency will be "working around the clock to make sure passengers get to their destination safely."
Secretary of Transportation Pete Buttigieg said Monday, "While we can't control the weather, we will be using every tool at our disposal to keep cancellations [and] delays as low as possible in the first place -- including working collaboratively with the airlines."
ABC News' Amanda Maile contributed to this report.