Nearly 40 million people are under a winter weather alert in south-central parts of the US, spreading from Tennessee to Texas.
A mix of freezing rain, sleet and bitter cold air has already hit parts of the region and is expected to last until mid-week.
More than 1,900 flights have been cancelled, with airports in Texas particularly affected.
Forecasts suggest "treacherous travel conditions" over the next few days.
On Tuesday morning, the National Weather Service predicted as much as half an inch of ice would accumulate on the roads in Austin and Dallas, Texas; Little Rock, Arkansas; and Memphis, Tennessee.
Arlington, Texas, police said they had responded to a seven-car pileup and a fatal car rollover. A second person died in a 10-car pileup in Austin, the city's fire department said.
Austin police also said on Tuesday they had responded to over 200 collision calls.
A sheriff's deputy in Travis County, Texas, was injured in a weather-related crash on Tuesday morning when he was hit by a truck while assisting a vehicle that had slid of the road, the sheriff's office said.
Several schools in Texas closed. As of Tuesday evening, more than 30,000 homes in the state had lost power.
This weather phenomenon is caused by an arctic cold frontal passage making its way south, where it is being confronted with warm and moist air from the Gulf of Mexico.
The result is wintry precipitation that is expected to drape over the region, the NWS said. The agency also expects heavy rain and scattered flash floods to hit parts of the Deep South and south-eastern US by midweek.
Meanwhile, the cold air mass will also hit the central and western regions of the US, where wind chills will send temperatures well below average to -40F (-40C). Temperatures in New England are also expected to drop to -30F and all the way down to -60F near the Canadian border.
As of Tuesday evening, nearly 2,000 US flights had been cancelled, affecting major airlines like Delta, American, United and Southwest, according to flight-data tracking website FlightAware. All the airlines have allowed passengers to rebook their flights without paying extra fees.