The Category 4 strike on the Keys, following Hurricane Harvey's landfall on the Texas coast as a Category 4 storm, makes this the first year in recorded history in which two Category 4 storms hit the United States.
About 30,000 people heeded orders to leave the Keys as the storm closed in, but an untold number refused, in part because, to many storm-hardened residents, staying behind in the face of danger is a point of pride.
The Florida Keys have suffered some minor damage and are expected to bear the brunt of the storm in the coming hours.
Some 6.5 million residents have been ordered to evacuate, Florida Governor Rick Scott said at a press briefing late Saturday. "There will be lots of debris, lots of trees that will be flying around and unfortunately they will be flying into our lines-we know that will occur". Protecting life is our top priority. "When I got to this neighborhood, I cried".
A tropical storm warning was issued for the first time ever in Atlanta, and school was cancelled in communities around the state.
"Possessions can be replaced".
The storm was expected to move along or near Florida's southwest Gulf coast by Sunday afternoon.
Battered and reeling from Hurricane Irma, isolated Caribbean islands lacking infrastructure, communications, medical supplies and other essentials prepared to weather another potent hurricane, Jose, as it bore down on the region Saturday.
With near-hurricane force winds lashing the Florida Keys starting around 8:00 pm (0100 GMT), the Miami-based National Hurricane Center (NHC) warned that "Irma is forecast to restrengthen" as it approaches mainland Florida.
At a weekend Cabinet retreat at Camp David in Maryland, President Donald Trump also cautioned people in Irma's path to "get out of its way" and not worry about possessions.
Jose, Katia are now hurricanes
The hurricane was located 145 miles south of Tampico, Mexico , and 115 miles west-northwest of Veracruz , Mexico . For Jose, the government of Antigua has issued a tropical storm warning for Antigua, Barbuda, and Anguilla.
Trump said all of America grieves for the lives already lost.
He added that the nation was grieving for those who've been killed by the powerful storm, which spent the week churning its way across the Caribbean, leaving death and destruction in its wake.
With an estimated 70,000 huddling in shelters statewide, the storm lashed the low-lying string of islands with drenching rain and knocked out power to close to 400,000 customers across the state.
Their own home is still under threat from the storm surge so they are staying at a friend's boarded-up home in a safer spot. "This is clearly a life-threatening situation". That was when the winds started to reach tropical storm force. But the big risk from this storm is really water, not wind.
Forecasters warned some places could see a storm surge of up to 15 feet (5 meters) of water. "When it happens, the storm water rushes in and rushes out". Media reports say shelters in some areas have been filling up quickly and some people have been turned away. "This is so important to families' safety".
Scott said that 1,700 Florida State Police troopers were on the road to help people get to shelters and that 2,500 nurses have volunteered to help in special-needs shelters. So when you look at it on the monitors here, it spans the entire Florida peninsula.
After leaving Florida, a weakened Irma is expected to push into Georgia, Alabama, Mississippi, Tennessee and beyond.
And Jose could produce up to an inch of additional rainfall on the island of Anguilla throughout the evening, which "will maintain any ongoing flooding", the hurricane center said.
"I will tell you in no uncertain terms - and I am not going to sugarcoat it - this is going to be a hard storm", Buckhorn said at the news conference.