Helene has made landfall in northwestern Florida as a Category 4 hurricane, with forecasters warning of a “catastrophic” storm surge.
High winds, possibly in excess of 130mph (209kph), and flash floods are possible, the US weather service said.
Category 4 hurricanes have sustained winds over 130 mph (209 kmh) that can bring down power lines and snap trees.
States of emergency have been declared in Florida, Georgia, and the Carolinas, with hurricane and flash flood warnings in place as far away as south-central Georgia.
Several Florida counties are under mandatory evacuation orders, and millions of people are under flood watch.
Storm surges, the wall of seawater pushed on land by hurricane-force winds, could be as high as 20 feet (6m), the weather service said and could be “catastrophic and unsurvivable” in Florida’s Apalachee Bay, south of Tallahassee.
There is also a risk of high winds and heavy rains, it said, calling the forecast “a nightmare surge scenario” for the bay and urging residents to “please, please, please take any evacuation orders seriously!”
More than 200,000 customers were without power in Florida, most along the west and east according to the logging website, poweroutage.
Tallahassee residents have been leaving their homes, many having stocked up on sandbags, food and supplies, Sky’s US partner NBC News reported.
The city’s mayor John Dailey urged people to take the warnings “extremely seriously”, calling Helene “the biggest storm in the history of the city to hit us head-on”.
Speaking to NBC News on Wednesday, Mr Dailey said though they are “very prepared”, he was also “very nervous, and I hope everyone is nervous”.
He added: “This is a big storm. It is going to cause a lot of damage.”
Jared Miller, sheriff of Wakulla County, went further – calling the oncoming storm “not a survivable event for those in coastal or low-lying areas”.
The county has issued a mandatory evacuation order, but one resident, Christine Nazworth from Crawfordville, which is located about 25 miles (40km) from Apalachee Bay, said her family would be sheltering in place.
She said: “I’m prayed up. Lord have mercy on us. And everybody else that might be in its path.”
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Leslie Powell, from Quincy, a city a similar distance from Tallahassee, told NBC she was leaving her mobile home to go to a shelter with her eight-month-old baby and six-year-old daughter.
She said simply: “I’m scared. I’ve got a lot of trees around my home, so it’s not safe for me and my kids.”