Ray Nagin said residents should leave the city in a staggered evacuation between 8:00 a.m. (13:00 GMT) and noon (17:00 GMT) on Sunday.
Speaking at City Hall, he called Gustav the "storm of the century," and said, "You need to be scared".
"I'm not sure we've seen anything like it," he added, also saying that, "Anyone who's thinking of staying, rethink it, get out of town."
Gustav, which overnight rampaged through western Cuba, is predicted to strengthen to a Category 5 storm over the Gulf. Some 300,000 people have been evacuated in Cuba, but there are as yet no reports that anyone has died.
Category 5 is the maximum on the scale, and Nagin said that Gustav was even more powerful than Hurricane Katrina, the storm which hit the city in 2005, killing some 1,800 people and causing hundreds of billions of dollars in damage. Nagin was mayor of New Orleans when Katrina devastated the city.
"The national weather service is saying that this is the worst possible storm that they can imagine," the mayor said.
