The center of the Category 1 hurricane was about 10 miles southwest of the mouth of the Mississippi River, the National Hurricane Center said at 8:05 p.m. EDT.
Isaac was forecast to gradually weaken as it moves inland, with heavy rains and dangerous surf conditions posing the biggest threats. Lakefront Airport in New Orleans was experiencing sustained winds of 45 miles per hour, gusting to 62 mph, and a storm surge of 8.8 feet was reported at Shell Beach.
Isaac hit land one day shy of the seventh anniversary of when Hurricane Katrina devastated New Orleans and a wide swath of the Gulf Coast, killing about 1,800 people.
In its wake, Isaac left 24 dead in Haiti, which still is recovering from a devastating earthquake two years ago.
Amtrak suspended train service to and from New Orleans on Tuesday and Wednesday, and authorities imposed a dusk-to-dawn curfew on residents of Plaquemines Parish, La., on the Gulf of Mexico coast, CNN reported.
In New Orleans, the U.S. Army Corps of Engineers closed the gate to the West Closure Complex -- among the world's largest pump stations.
A hurricane warning was in effect for the Louisiana coast east of Morgan city to the Mississippi-Alabama border and a hurricane watch was in effect from Intracoastal City to Morgan City, La. Tropical storm warnings were in effect from the Mississippi-Alabama border east to Destin, Fla. Tropical storm watches were in effect from High Island, Texas, to Cameron, La.
Hurricane-force winds gusting up to 130 mph had extended out as far as 60 miles from the center and tropical storm winds extended out 185 miles from the storm's center.
A storm surge of as high as 12 feet was predicted for high tide along the Mississippi and southeastern Louisiana coasts, with 4 to 8 feet predicted for Alabama, 3 to 6 feet for southcentral Louisiana and the Florida panhandle, 2 to 4 feet for Apalachee Bay and 1 to 3 feet for the remainder of Florida's west coast.
"Surge-related flooding depends on the relative timing of the surge and the tidal cycle and can vary greatly over short distances," the hurricane center said.
The storm was expected to produce 7 to 14 inches of rain with 20 inches possible in some areas of southeastern Louisiana, southern Mississippi, southern Alabama and the extreme western portion of the Florida Panhandle.
President Obama Tuesday urged area residents to heed warnings from local officials to head to higher ground. In Mississippi, 1,500 National Guard troops have been ordered into the state's southern counties to help with emergency operations.
Forecasters are also watching Tropical Storm Ileana off the western coast of Mexico. It was about 1,270 miles east-southeast of the Lesser Antilles and 1,400 miles southwest of the Azores, at 5 p.m. EDT. The system had maximum sustained winds or 35 mph and was moving west-northwest at 10 mph, away from land.
No coastal watches or warnings are in effect for Ileana.
Republican leaders at the party's national convention in Tampa, Fla., expressed concern Isaac's striking around the Katrina anniversary could remind voters of the George W. Bush administration's response, which party officials admitted was a symbol of collective GOP incompetence they don't want to revive.