Milton is now a Category 4 hurricane and its outer bands will start lashing Florida's west coast by Wednesday morning.
It could be one of Florida's worst storms in 100 years, President Joe Biden warned while addressing the media on Tuesday.
RELATED: Tampa Bay hasn't been hit directly by a major hurricane since 1921. Milton may be the one
Race to escape Hurricane Milton as storm closes in on Florida
Milton could not only enter Florida's west coast as a hurricane but could still be hurricane-strength by the time it leaves Florida's east coast, he said.
If you are under evacuation orders, leave now, Biden urged, stressing that it's "a matter of life and death."
The system is threatening the densely populated Tampa metro area - which has a population of more than 3.3 million people - with a potential direct hit and menacing the same stretch of coastline that was battered by Helene.
"While fluctuations in intensity are expected, Milton is forecast to remain an extremely dangerous hurricane through landfall in Florida," the National Hurricane Center said in a 1 a.m. ET update on Tuesday.
While preparing for Milton, the government is still "surging resources" in states impacted by Hurricane Helene, he said.
Biden said he spoke to Florida Gov. Ron DeSantis on Monday.
"He said he's got all that he needs," Biden said, adding that he gave the governor his "personal phone number to call."
Biden also slammed individuals spreading misinformation around FEMA's response to Hurricane Helene, calling it "un-American."
Traffic was thick on Interstate 75 heading north Monday as evacuees fled in advance of the Milton. Crews are also hurrying to clear debris left by Helene.
When will Milton make landfall?
According to the National Hurricane Center's Live Hurricane Tracker, Milton will make landfall on the west coast of Florida late Wednesday. It's expected to be a Category 3 storm, which have winds of 111-129 mph (180-210 kph), when it hits the shore in the Tampa Bay region, which has not endured a head-on hit by a major hurricane in more than a century.
It could retain hurricane strength as it churns across central Florida toward the Atlantic Ocean. That track would largely spare other states ravaged by Helene, which killed at least 230 people on its path from Florida to the Carolinas.
How strong will it be?
Milton intensified quickly over the eastern Gulf of Mexico. Florida Gov. Ron DeSantis told reporters Monday afternoon the hurricane was far stronger than what was predicted two days ago.
Tracking Hurricane Milton: Florida bracing for powerful storm
Milton was a Category 5 hurricane with maximum sustained winds of 180 mph (285 kph) and was centered about 675 miles (1,085 kilometers) southwest of Tampa at late afternoon on Monday.
Those winds eased to 155 mph (250 kph) by early Tuesday and the hurricane was downgraded to Category 4 status. The National Hurricane Center said Milton still posed "an extremely serious threat to Florida."
How bad is damage expected to be?
The entire Gulf Coast of Florida is especially vulnerable to storm surge.
Hurricane Helene came ashore some 150 miles (240 kilometers) away from Tampa in the Florida Panhandle and still managed to cause drowning deaths in the Tampa area due to surges of around 5 to 8 feet (1.5 to 2.5 meters) above normal tide levels.
Tampa Bay is forecast to face a record-breaking storm surge of 10 to 15 feet. That's the highest ever predicted for the location and nearly double the levels reached two weeks ago during Helene, said National Hurricane Center spokeswoman Maria Torres.
Storm surge in Fort Myers could reach 6 to 10 feet.
As Milton moves over Florida, winds ahead of the system could push storm surge up to 5 feet in Jacksonville and up to 4 feet in Savannah.
Wind gusts could climb over 130 mph in the St. Petersburg area.
Up to 18 inches of rain is possible by the end of the storm.
What if I have travel plans to that part of Florida?
Tampa International Airport said it will stop flights at 9 a.m. Tuesday. The airport posted on X that it is not a shelter for people or their cars.
RELATED: Hurricane Milton travel impacts: Airport closures and more
St. Pete-Clearwater International Airport said it is in a mandatory evacuation zone and will close after the last flight leaves Tuesday.
How is Mexico preparing?
Mexican officials are organizing buses to evacuate people from the low-lying coastal city of Progreso on the Yucatan Peninsula after Mexico's National Meteorological Service said Hurricane Milton "may hit between Celestun and Progreso" late Monday or early Tuesday.
Celestun, on the western corner of the peninsula, is a low-lying nature reserve home to tens of thousands of flamingos. Progreso, to the east, is a shipping and cruise ship port with a population of about 40,000.
Tropical Storm Leslie and other things to watch in the tropics
Tropical Storm Leslie continues to track northwest across the open central Atlantic. No direct impacts to land are expected from this storm, but shipping interests should monitor its progression.
AccuWeather hurricane experts are monitoring a low risk for development over the next few days off the southwestern coast of Bermuda.
Experts are also monitoring a low risk for development during the middle to later parts of this week west of the Cabo Verde Islands, as well as another low-risk development over the western Caribbean next week.
Kirk will continue to lose wind intensity over open waters as it heads toward western Europe, bringing impacts to portions of western Europe late this week as a tropical wind and rainstorm.
RELATED: How to help those impacted by Hurricane Helene: Charities, organizations to support relief efforts
ABC News and The Associated Press contributed to this report.