Isaac reached hurricane force late Monday morning as it veers toward New Orleans.
An evacuation order came Tuesday in Harrison County, which is in the center and has the largest population. The orders came Monday in Hancock County, which borders Louisiana; and Jackson County, which borders Alabama.
The Mississippi Gaming Commission ordered the closing of all coast casinos, which are on or near the water.
In Hancock County Tuesday, motorists crept through waves washing across Beach Boulevard in the small town of Waveland.
Meanwhile, people who don't have cars or can't drive are being transported to shelters. Harrison County Emergency Operations Director Rupert Lacy says nearly 600 people requested rides.
The Gulfport-Biloxi International Airport is suspending all incoming and outgoing flights before noon Tuesday due to the approach of Isaac.
Airport executive Clay Williams says the airport will probably close Wednesday, but flights are scheduled to resume Thursday.
The airport is served by five airlines that offer nonstop service to Atlanta, Charlotte, Dallas/Ft. Worth, Houston, and St. Petersburg/Clearwater.
Barriers built with BP money to stop the Gulf oil spill in 2010 could prove effective against storms like Isaac.
That is at least the hope on Dauphin Island, Alabama's largest barrier island, where island and state officials have used money from the oil giant to build dunes and a rock wall.
Louisiana officials, meanwhile, have spent more than $200 million on sand berms off their state's coast.
Although the work in Alabama and Louisiana was touted as a way to stop oil from flowing into sensitive marshlands, local officials now see the structures as part of a broader coastal restoration.
Officials are worried that Isaac could stir up tar and oil left behind from the spill, though no one really knows how much remains hidden.