Hurricane Isaac will hit the Louisiana city exactly seven years after it was devastated by Hurricane Katrina, but it is a much less powerful storm.
New Orleans has closed its new floodgates in a bid to protect it from the effects of high waters brought by sustained winds of up to 80 mph (130 km/h).
Isaac killed at least 24 people in Haiti and the Dominican Republic.
It has also caused significant flooding and damage across the Caribbean and forced a day’s delay to the start of the Republican party’s congress in Tampa, Florida.
At 02:00 local time the Category One hurricane was almost stationery about 70 miles (110 km) south of New Orleans, according to the US National Hurricane Centre (NHC).
Tens of thousands of people have been told to leave their homes in low-lying areas of Louisiana and Mississippi, though a mass evacuation has not been ordered. Storm warnings are also in place in parts of Florida, Texas and Alabama.
Officials say Isaac is likely to weaken before it reaches New Orleans.
“We don’t expect a Katrina-like event, but remember there are things about a Category One storm that can kill you,” said New Orleans Mayor Mitch Landrieu.
Of particular concern are storm surges, with peaks of up to 3.7 m (12ft) forecast in parts of Mississippi and southeastern Louisiana. Rainfalls of up to 50 cm (20 inches) are forecast across wide areas, along with a high chance of isolated tornadoes along the coast.
The bowl-shaped city of New Orleans is particularly vulnerable to storms, with the centre of the city the furthest below sea-level.
But Mitch Landrieu said that the 8m-high levee gate which now protects the areas of the city that were badly flooded in 2005 had been closed since Tuesday morning.
Many residents of New Orleans have chosen to secure their homes but stay put, saying they were not too concerned by Isaac.
“I feel safe,” said Pamela Young from her home in the Lower Ninth Ward, a neighborhood devastated by Katrina.
“Everybody’s talking <<going, going>>, but the thing is, when you go, there’s no telling what will happen. The storm isn’t going to just hit here.”
“If the wind isn’t too rough, I can stay right here. If the water comes up, I can go upstairs.”
Nazareth Joseph, who works at a hotel in French Quarter and was in the city during Katrina, said he had a busy week ahead so would stay where he was.
“We made it through Katrina; we can definitely make it through this. It’s going to take a lot more to run me. I know how to survive,” he told the Associated Press news agency.
By Tuesday night, more than 58,000 homes in New Orleans were reported to have lost power. Outages have also been reported across Louisiana and Mississippi, affecting more than 200,000 homes and business.
President Barack Obama has declared an emergency in Louisiana and Mississippi, allowing federal funds to be released to local authorities.
Speaking from the White House, he warned residents along the Gulf Coast to heed warnings, including those to evacuate, saying: “Now is not the time to dismiss official warnings. You need to take this seriously.”
Shortly before Isaac reached hurricane status on Tuesday, Louisiana Governor Bobby Jindal said the emergency declaration fell short of the federal help he had asked for.
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