The US National Weather Service is predicting the nor'easter will bring heavy snow, powerful winds and widespread coastal flooding starting Monday and lasting through Tuesday.
A blizzard warning has been issued for a 400-kilometer stretch of the Northeast, including New York and Boston.
Some 5,000 flights in and out of the region have been cancelled.
At least 28 million people will face blizzard conditions and an estimated 50 million could see more than 30 centimeters of snow.
New York Governor Andrew Cuomo has declared a state of emergency.
"There will be dangerous and difficult conditions – difficult to clear, difficult for the plows. I am declaring a state of emergency affected immediately."
In New York City, officials are warning the storm could be one of the most powerful blizzards ever recorded. Weather forecasters say the city could see as much as 60 centimeters of snow by Tuesday morning.
Mayor Bill de Blasio says only emergency vehicles will be allowed on city streets starting from 11 p.m. Monday night, and the order will be in place until the situation is considered safe.
"The bottom line here is as thousands and thousands of people are working for this city, are gonna out there doing a lot to keep us safe. We have to keep each other safe. We have to look after each other. We also have to do the right thing by getting off the streets and staying indoors so they can do their work."
All public schools in the city will be closed on Tuesday. All after-school activities and programs scheduled for Monday have already been canceled.
Workers clearing the snow in New York City will work 12-hour shifts, with roughly 24-hundred workers on each shift.
The city has deployed nearly 2-thousand plows to clear almost 10-thousand kilometers of roadways.
Some residents have already begun stocking up on food, water, and other essential items.
The authorities are suggesting residents should avoid outdoor activities.
For CRI, I'm Su Yi in New York.
