- A shelter of last resort set up in the Middle Keys city of Marathon was reported to be without power or running water, and surrounded by surging waters.
Irma is so wide that authorities faced destructive storm surges on both coasts of Florida and the Keys as Irma follows a path north toward Georgia.
The NHC also warned of tornado risks through Sunday night, with the greatest threat in areas east of the storm's path.
Hurricane Irma lashed the Florida mainland on Sunday, where anxious residents dreaded being "punched in the face" by the monster storm after it whipped the Keys island chain with fearsome wind gusts.
Six million people — one third of the state's population — have been ordered to flee the path of the hurricane, which weakened to a Category Two storm as it churned past the Keys, packing top winds of 110 miles (177 kilometers) per hour.
At 3.35 pm (1935 GMT), the storm made its second Florida landfall, hitting Marco Island near the popular shopping and golf destination of Naples, hours after striking the Keys island chain.
"It's going to be horrible," Florida Governor Rick Scott said on NBC's "Meet the Press."
"Now we have to hunker down and watch out for each other," he said.
After a cabinet briefing from Homeland Security and emergency officials, President Donald Trump said he would travel to the state "very soon."
"Right now, we're worried about lives, not cost," he said.
Bob Buckhorn, mayor of the low-lying city of Tampa, was blunter: "We are about to get punched in the face by this storm."
One of the mightiest hurricanes ever to slam storm-prone Florida, Irma is threatening dangerous storm surges of up to 15 feet (4.5 meters), enough to cover a house, as it collides with the state after sowing devastation through the Caribbean.
"I am concerned about people that don't believe in the storm surge," said Virginia Defreeuw, 76, who fled from her mobile home in Naples to a shelter. "You need to be afraid of the storm surge! People are not listening."
In Miami, the storm brought at least two construction cranes crashing down, while the glitzy Brickell neighbourhood was flooded.
Steven Schlacknam, a 51-year-old visual artist staying in a 37th floor apartment, said the waters were "coming over the sea walls."
"The wooden pier is basically gone," he told AFP.
At least 30 deaths are attributable to the storm, including three in Florida.
The US victims included a sheriff's deputy killed in a head-on collision early Sunday as she drove home to get supplies after working in a shelter all night.
With its high winds and rains now impacting all of south Florida, the storm is currently moving up along Florida's western Gulf coast from Naples to Fort Myers and the densely populated Tampa Bay peninsula.
Irma closed in on the coast after ripping boats from their moorings, flattening palm trees and tearing down power lines across the Key West island chain popular for fishing and scuba diving.