The U.S. National Hurricane Center says the storm's center reached land at 7:45 p.m. in Plaquemines Parish, about 90 miles southeast of New Orleans.
The outer bands of the storm brought big waves, strong winds and significant rain. Officials say widespread flooding and damage is likely.
The storm's arrival Tuesday night comes on the eve of the seven-year anniversary of Hurricane Katrina, which devastated the region. Officials in Louisiana and neighboring states say they are far better prepared for this storm than they were for Katrina.
Isaac, a massive storm spanning nearly 200 miles from its center, could dump as much as 20 inches of rain. This will be a big test for the area since the levees failed in New Orleans during Katrina. Isaac isn't going to be as strong as Hurricane Katrina, but still, many decided not to take the chance.
Federal Emergency Management Agency officials said the levees have been fortified since Katrina and are equipped to handle storms stronger than Isaac. But not everyone wants to take the chance. Some military bases in the Gulf region prepared by sending their planes elsewhere for safekeeping.
President Barack Obama said residents of the Gulf Coast should listen to local authorities and follow their directions as Isaac approaches.
"Now is not the time to tempt fate. Now is not the time to dismiss official warnings. You need to take this seriously," the president said.
Evacuations were ordered in Mississippi's coastal counties and the closure of its 12 shorefront casinos. People across the region have boarded up homes and schools, and universities and businesses are closed.
Many residents along the Gulf Coast opted to ride it out in shelters or at home and officials, while sounding alarm about the dangers of the powerful storm, decided not to call for the mass evacuations like those that preceded Katrina, which packed 135 mph winds in 2005.
While Isaac is taking direct aim on New Orleans, the impact will be felt well beyond the city limits. All commercial flights in and out of New Orleans have been canceled and oil refineries in the Gulf have also been shut down.
The Associated Press contributed to this report.