Those planning to ride out the storm snapped up canned food, water and generators, while military helicopters and planes were flown out of the area and Cape Canaveral's Kennedy Space Center said it would close on Thursday.
Forecasters said the still-strengthening Category 4 storm could hit on Labor Day weekend as early as Friday night, less than three weeks after Charley raked Florida's western coast with 145 mph wind, causing billions of dollars in damage and killing 27 people.
"Frances will threaten the U.S. mainland probably on Saturday," says CBS News Meteorologist George Cullen. "Right now, it looks to be a Florida storm, meaning a landfall somewhere along the coast of Florida later Saturday. If it's farther up the coast, it would be Saturday night into Sunday."
"I can't emphasize enough how powerful this is. If there's something out there that's going to weaken it, we haven't seen it," National Hurricane Center director Max Mayfield said.
Gov. Jeb Bush and Georgia Gov. Sonny Perdue declared states of emergency, activating the National Guard. Bush also warned more evacuations may be ordered.
Many homes in southwest Florida still have blue tarps patching holes in their roofs after Charley, and some streets remain full of storm debris that could become wind-blown projectiles.
"We've just gone through 2½ weeks of torture trying to get our lives back to some sense of order," said Punta Gorda retiree Tom Hamilton.
Evacuation orders were posted for 300,000 residents in coastal areas of Palm Beach County, and nearly 200,000 were told to leave mobile homes and low-lying areas of Brevard, Martin and Indian River counties, which could be hit by tremendous ocean waves. The evacuation orders were set to take effect Thursday afternoon.
Frances was about 650 miles southeast of Florida Wednesday evening, heading northwest on a course that would take it to the central portion of Florida's eastern coast. Residents of Georgia, North Carolina and South Carolina watched the forecast closely in case Frances took a sharper turn to the north.
Bush cautioned that "all the science in the world and all the technology in the world isn't going to be able to pinpoint exactly where the storm goes."
Frances would be the fourth storm to affect Charleston, S.C., this summer. Bonnie and Charley arrived within days of each other in August, and Gaston dumped more than 13 inches of rain in some areas when it came ashore Sunday.
With the ground saturated from previous storms, more rain and the slightest wind could cut utility service for thousands, even if they don't take a direct hit from the storm.
"With the ground this wet, trees could easily topple," said Tom Williams, a spokesman for Duke Power in Charlotte, N.C.
The storm and the mass evacuations are sure to spoil Labor Day outings and make a mess of holiday travel across the Southeast. Florida may reverse lanes on some highways to handle the evacuation traffic, state Emergency Management Director Craig Fugate said.
If Frances hits, it could be the most potent two-hurricane combination to hit a single state in at least a century of record-keeping. Frances is as strong as Charley, but forecasters said it could become a Category 5 with winds of 156 mph or higher.
Hurricane-force winds extended about 80 miles from Frances' center, making it about twice the width of Charley and increasing the possibility for damage.
The last time two major hurricanes hit Florida in rapid succession was 1950. Hurricane Easy struck Tampa around Sept. 4 of that year and Hurricane King hit Miami six weeks later on Oct. 17. They were Category 3 storms.
Nancy Cuffaro of Port Charlotte, whose home and pizza restaurant were damaged by Charley, said she is hoping Frances spares an area that is still suffering.
"I know we can't withstand too much. I really don't know what to think here. I'm lost. It's starting to get to me," she said.
A Home Depot to the south in Florida City, hit hard by Hurricane Andrew 12 years ago, more than doubled its daily sales and ran out of generators and plywood. It sold $50,000 worth of lumber Tuesday, said assistant manager Lisa Ftiffler.
North Miami Beach resident Lorraine Lewis bought a small cooking stove in case of emergency but wasn't planning to stick around long enough to use it.
"I have water and plastic and a plane ticket," she said.
State officials worried about finding enough room in shelters. Many hotel rooms in southern Florida are occupied by emergency workers and people left homeless by Charley. Some schools and community centers are still being used as shelters.
Deanna Creamer, who rode out Charley in her house in Punta Gorda, was still repairing roof and water damage. "I heard a little bit on the radio this morning, and I shut it off," said Creamer, 40. "I just can't imagine having to go through this again."
Charley destroyed or heavily damaged more than 30,000 homes and caused an estimated $7.4 billion in insured damage. It was the worst natural disaster to hit Florida since Andrew caused $15.5 billion in insured damage and killed 15 people.