At least three tornadoes have touched down in southern Louisiana, ripping houses from their foundations, downing electricity lines and leaving 10,000 homes without power.
Dozens of injuries were reported, but no fatalities.
New Orleans Mayor Mitch Landrieu said at least two of the injured were seriously hurt after severe storms brought hail, high winds and twisters to the city.
The storm flipped over cars, tore roofs from homes, ripped through a petrol station canopy, knocked down pylons and turned a truck upside-down.
The wall of severe weather lit up radar and prompted tornado warnings across the region on Tuesday.
The national Storm Prediction Centre in Norman, Oklahoma, said 2.7 million people in parts of Louisiana, Mississippi and Alabama would be at the highest risk.
Press Secretary Sean Spicer said the White House was monitoring the severe weather, and President Donald Trump would be reaching out to local and state officials throughout the day.
Other twisters struck near the town of Donaldsonville and in the town of Killian, National Weather Service meteorologist Danielle Manning said.
At least seven homes have been damaged in Livingston Parish, north-west of New Orleans, where other minor injuries were reported, said Brandi Janes, the deputy emergency preparedness director.
"Two of them are completely gone... all the way to the ground," she said, adding that crews were removing trees from roads and working with the Red Cross to get help to damaged areas.
One warning described a "large, extremely dangerous and potentially deadly" twister south of Hammond, Louisiana.