About 1,000 U.S. National Guard troops in military vehicles took up positions on the city's mostly deserted streets, brandishing automatic assault rifles to ward off any threat of looting.
Isaac spared Tampa, Florida, where the Republican National Convention began on Monday. But it forced party leaders to revamp their schedule. They may have to make further revisions so as not to be seen celebrating Mitt Romney's presidential nomination while Gulf Coast residents struggle through the storm.
President Barack Obama urged residents to take cover and heed warnings, saying that now was "not the time to tempt fate." . He issued emergency declarations for Louisiana and Mississippi earlier this week.
On Tuesday morning, army engineers closed the massive new floodgate at Lake Borgne, east of New Orleans, for the first time. It is largest storm-surge barrier in the world.
In other preparations, oil production in the U.S. Gulf of Mexico nearly ground to a halt, and ports and coastal refineries curtailed operations.
At 7 p.m. CDT (2400 GMT), the Hurricane Center said Isaac was centered about 90 miles (140 km) southeast of New Orleans with top sustained winds of 80 miles per hour (130 kph).
The storm was traveling at a relatively slow 8 mph (13 kph). The sluggish pace is a concern for people in its path since slow-moving cyclones can bring higher rainfall.
Isaac was about 370 miles (595 km) wide. Hurricane-force winds extend outward up to 60 miles (97 km) from the center of the storm. Heavy rains and big storm surges were also forecast for parts of Mississippi, Alabama and the Florida Panhandle.
Nearly 70,000 people in Louisiana were without electricity.