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.
Isaac comes almost exactly seven years to day after Katrina hit New Orleans on Aug. 29, 2005, killing more than 1,800 people and causing billions of dollars of damage.
The Army Corps of Engineers has since built a $14.5 billion defense system of walls, floodgates, levees and pumps designed to protect the city from a massive tidal surge like that which swamped New Orleans in Katrina's wake.
Most of the city's Lower Ninth ward, still scarred by the devastation of Katrina, was deserted on Tuesday. Residents who had not evacuated stocked up on water, food and fuel.
"We've got all kinds of eats and treats," Arthur Anderson, 61, who was trapped in the attic of his house during Katrina before he escaped by boat.
Authorities have urged thousands of residents in low-lying areas to leave, warning that the storm could flood towns and cities in Mississippi and Alabama, as well as Louisiana, with a storm surge of up to 12 feet (3.7 meters).