Irma has strengthened to a category 4 hurricane as it approaches Florida, with maximum sustained winds of 130mph.
Wind gusts close to hurricane force are already battering islands in south Florida, with the mainland due to be hit in the coming hours.
Water levels are already rising on Florida coast, where a huge storm surge is expected.
At least 25 people died when hurricane Irma earlier hit several Caribbean islands.
In Florida, 6.3 million people – about 30% of the state’s population – had been told to evacuate. However, on September 9, Florida Governor Rick Scott said it was now too late to leave for anyone remaining.
The National Hurricane Center (NHC) warns that a “life-threatening storm surge” is expected in the Florida Keys – a chain of small islands in Florida’s south – and also the west coast of Florida.
Residents in the Caribbean islands have made last-minute preparations for Hurricane Irma, the most powerful Atlantic storm in a decade, with officials warning of its “potentially catastrophic” effects.
Irma, a category 5 hurricane, the highest possible level, has sustained wind speeds reaching 185mph.
The hurricane is starting to hit the Leeward Islands and will move on towards Puerto Rico and the Dominican Republic.
In the US, Florida’s Key West area has ordered a mandatory evacuation.
Visitors will be required to leave on September 6, with residents due to follow in the evening, and the international airport will halt all flights.
Martin Senterfitt, the emergency operations centre director in Monroe County in Florida, said: “We’re emphatically telling people you must evacuate. You cannot afford to stay on an island with a category five hurricane coming at you.”
Closer to the storm, thousands of people have been evacuated from at-risk areas. Residents have flocked to shops for food, water, and emergency supplies, and in several locations goods were already in short supply.
Airports have closed on several islands, popular holiday destinations, and authorities have urged people to go to public shelters.
President Donald Trump has declared a state of emergency for Florida, Puerto Rico and the US Virgin Islands, mobilizing federal disaster relief efforts for those areas.
In Puerto Rico, a 75-year-old man died during preparations for the storm, which has been described by Governor Ricardo Rossello as “something without precedent”.
Storm surges, life-threatening winds and torrential rainfall are expected along the Leeward Islands, which include Antigua, Barbuda and Anguilla.
Parts of Texas and Louisiana are dealing with the damage done by Hurricane Harvey last month. But it is not yet clear what impact Hurricane Irma might have on the US mainland.
The mainland has not been hit by two category 4 hurricanes in one season since the storms were first recorded in 1851.
A third tropical storm, Jose, has formed further out in the Atlantic behind Irma, and is expected to become a hurricane later on in the week.