Hurricane Nate has made landfall near the mouth of the Mississippi River in Louisiana, the US National Hurricane Center (NHC) says.
The storm, with maximum sustained winds of 85mph (137km/h), is moving north, and a second landfall is expected on the Mississippi coast later.
Louisiana, Mississippi, Alabama and parts of Florida have issued hurricane warnings and evacuation orders.
Nate killed at least 25 people in Nicaragua, Costa Rica and Honduras.
The tropical storm has since strengthened and is now a category one hurricane on the Saffir-Simpson scale.
Although not as strong as last month's Maria and Irma, Nate is expected to bring strong winds and storm surges.
US President Donald Trump earlier issued an emergency declaration for Louisiana, allowing the state to seek federal help with preparation and possible relief efforts.
In Alabama, Republican Governor Kay Ivey has urged residents in areas facing heavy winds and storm surges to take precautions.
Five ports along the Gulf Coast have also been closed to shipping as a precaution.
Most oil and gas platforms in the US Gulf of Mexico have evacuated their staff and stopped production ahead of the storm.
The hurricane warning issued to parts of the Gulf Coast includes the threat of life-threatening storm surge flooding. Evacuation orders have been put in place for some low-lying areas.
Louisiana Governor John Bel Edwards has declared a state of emergency ahead of the hurricane.
He said more than 1,000 National Guard troops had been mobilised with a number sent to New Orleans to monitor the drainage pumps there. "Anyone in low-lying areas... we are urging them to prepare now," he said.
A mandatory curfew from 18:00 (23:00 GMT) is in place in New Orleans, where residents from areas outside the city's levee system have been evacuated.
"Nate is at our doorstep, or will be soon," the city's Mayor Mitch Landrieu said, adding that the winds could cause significant power outages.
"We have been through this many, many times, there is no need to panic," he added.
A tropical storm warning is currently in effect for New Orleans.
Nate went past Mexico's Yucatan Peninsula - home to the popular beach resorts of Cancun and Playa del Carmen - on Friday night as it headed north, the NHC said.
Nate caused heavy rains, landslides and floods which blocked roads, destroyed bridges and damaged houses as it tore through central America.
At least 13 people died in Nicaragua, eight in Costa Rica, three in Honduras and one in El Salvador.
The tail of the storm is still causing problems in the region, where thousands have been forced to sleep in shelters and some 400,000 people in Costa Rica were reported to be without running water.
Photo copyright: GETTY IMAGES (Caption: New Orleans residents fill sandbags as Nate blows in)