North Carolina, South Carolina, Virginia and Maryland have all declared a state of emergency and told residents to prepare for flooding and power outages.
Packing winds of up to 220 km/h (140 mph) late Monday, Florence was expected to further strengthen and become "an extremely risky major hurricane" by the time in makes landfall in the Carolinas on Thursday, the National Hurricane Center (NHC) said in a 21:00 UTC update.
The coastal surge from Florence could leave the eastern tip of North Carolina under more than 9 foot of water in spots, projections showed. The model appears to show the hurricane stalling, dumping rain as it sits on the state's edge.
Motorists were streaming inland on highways converted to one-way evacuation routes after forecasters and politicians pleaded with the public to take the warnings seriously.
The NHC said the first tropical storm-force winds of at least 39 miles per hour (63 kph) would hit the region early on Thursday with the storm's centre reaching the coast Friday.
North Carolina Governor Roy Cooper warned that "disaster is at the doorstep", and "tens of thousands" of buildings may be flooded.
He added: "The waves and the wind this storm may bring is nothing like you've ever seen. Don't bet your life on riding out a monster".
More than 5.4 million people live in areas under hurricane warnings or watches on the US East Coast, according to the NWS, and another four million people were under a tropical storm watch.
If this scenario plays out, meteorologists say there would be monumental rainfall totals along the coast and just inland east of the eye's landfall location.
Federal officials begged residents to put together emergency kits and have a plan on where to go. It's going to destroy infrastructure.
Jeff Byard of the Federal Emergency Management Agency (FEMA) invoked a former boxing champion to warn residents that it would bring "a Mike Tyson punch to the Carolina coast".
Some 38cm (15in) to 64cm (25in) of rain is forecast in some areas - with up to one metre (40in) at the centre of the storm. "It's going to have tremendous impact on our weather and local conditions".
He tweeted: "We got A Pluses for our recent hurricane work in Texas and Florida (and did an unappreciated great job in Puerto Rico, even though an inaccessible island with very poor electricity and a totally incompetent Mayor of San Juan)".
Sunday night into Monday morning, wind speeds in Middle Georgia could increase to 20-40 miles per hour.