The storm held a potential surge of 5.5m to 8.5m that would easily top New Orleans' hurricane protection levees, as well as bigger waves and as much as 38cm of rain.
A hurricane warning was in effect for the north-central Gulf Coast from Morgan City, Louisiana, to the Alabama-Florida line. Tornado warnings were posted for Louisiana, Mississippi, Alabama and Florida.
For years, forecasters have warned of the nightmare scenario a big storm could bring to New Orleans, a bowl of a city that's up to 3m below sea level in spots and dependent on a network of levees, canals and pumps to keep dry from the Mississippi River on one side, Lake Pontchartrain on the other.
The fear is that flooding could overrun the levees and turn New Orleans into a toxic lake filled with chemicals and petroleum from refineries, as well as waste from ruined septic systems.
Nagin said he expected the pumping system to fail during the height of the storm. The mayor said the US Army Corps of Engineers was standing by to get the system running, but water levels must fall first.
"We are facing a storm that most of us have long feared," he said. "This is a once-in-a-lifetime event."
Major highways in New Orleans cleared out late on Sunday after more than 24 hours of jammed traffic as people headed inland. At the peak of the evacuation, 18,000 people an hour were streaming out of southeastern Louisiana.
On inland highways in Louisiana and Mississippi, heavy traffic remained the rule into the night as the last evacuees tried to reach safety.
In Washington, the Nuclear Regulatory Commission said it has been advised that the Waterford nuclear plant about 32km west of New Orleans has been shut down as a precautionary measure.
New Orleans hasn't taken a direct hit from a hurricane since Betsy in 1965, when an 2.25m to 3.3m storm surge submerged parts of the city in 2.2m of water. Betsy, a Category 3 storm, was blamed for 74 deaths in Louisiana, Mississippi and Florida.
Evacuation orders also were posted all along the Mississippi coast, and the area's casinos, built on barges, were closed early Saturday. Bands of wind-whipped rain increased on Sunday night and roads in some low areas were beginning to flood.
"Hopefully it will take a turn and we'll be spared the brunt of it, but it just don't look like that," said James Bosco, who was packing up a final few items from his beachfront apartment in Gulfport. "I just hope everybody makes it all right. We can always rebuild."
Alabama officials issued mandatory evacuation orders for low-lying coastal areas.
Katrina hit the southern tip of Florida as a much weaker storm on Thursday and was blamed for nine deaths. It left miles of streets and homes flooded and knocked out power to about 1.45 million customers. It was the sixth hurricane to hit Florida in just over a year.
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