ST. PETERSBURG, Fla.—Millions of people along Florida’s Gulf Coast are bracing for Hurricane Milton, a historically powerful storm that is expected to make landfall Wednesday evening and wallop a region still reeling from Hurricane Helene.

ofia Andreeva and her uncle Ivaylo Kanchev board up their home ahead of the arrival of Hurricane Milton in St. Petersburg, Florida, U.S., October 8, 2024. REUTERS/Octavio Jones

Debris left from Hurricane Helene lays on the beach before the arrival of Hurricane Milton, St. Pete Beach, Florida, U.S., October 7, 2024. REUTERS/Octavio Jones/File Photo

Milton strengthened to a Category 5 storm overnight, with wind speeds of up to 160 miles an hour. As of 5 a.m. ET, the storm was about 300 miles southwest of Tampa, Fla., according to the National Hurricane Center. It is expected to hit the west coast of Florida late Wednesday or early Thursday, battering it with hurricane-force winds, life-threatening storm surge and heavy rain.

People board up businesses as Hurricane Milton approaches Fort Myers, Florida, U.S. October 8, 2024. REUTERS/Ricardo Arduengo/File Photo

It will likely compound the damage from Helene, which left a path of death and destruction across several states after striking Florida as a Category 4 storm less than two weeks ago. Some areas are still littered with debris that could become projectiles once Milton arrives.

“If you’re going to get out, get out now,” Florida Gov. Ron DeSantis said Tuesday afternoon.

Tampa Bay is bracing for the possibility of a direct hit. It would be the first time a major hurricane has struck the region since 1921. The area, which is densely populated, fast-growing and has seen booming development on low-lying ground, is one of the most vulnerable in the U.S. to coastal flooding.

More than three million people live in the Tampa Bay metropolitan area, which includes the cities of Tampa, Clearwater and St. Petersburg. Some evacuees faced heavy traffic and encountered gas stations without fuel as they attempted to escape the storm.

“This is not survivable,” said Cathie Perkins, the director of emergency management for Pinellas County, where Clearwater and St. Petersburg are located.

“This is the ocean coming into your living rooms,” Perkins said. “This is fast-rising water with a lot of pressure behind it, so don’t think you’re going to be able to ride that out.”

Many businesses in St. Petersburg were closed Tuesday, with plywood covering storefronts. Residents hurried to pick up last-minute supplies from the few stores still open.

Motorists lined up to enter a Publix parking lot while shoppers inside grabbed bottled water, batteries, charcoal and other goods. One shopper added a couple of chocolate bars to her purchases and said, “It doesn’t count if there’s a hurricane coming.” Strangers shared plans and conversations ended with, “Stay safe!”

Storm surge, heavy wind, life-threatening flooding

Tampa Bay and its coastal neighbors could receive up to 15 feet of storm surge, the hurricane center said. Heavy rainfall is also expected in the central and northern portions of the peninsula, with some areas expected to receive as much as 18 inches, the hurricane center said, warning that life-threatening flooding was possible.

Officials have issued mandatory evacuation orders in almost every county on the western side of the peninsula, and local officials have urged residents to leave as quickly as possible.

Fleeing the areas proved challenging for some. Traffic jams on Monday gave way to a shortage of fuel on Tuesday. More than 1,300, or about 17%, of the state’s gas stations had run out of fuel on Tuesday night, according to GasBuddy. In the Tampa and St. Petersburg area, 47% lacked fuel, GasBuddy said.

The Florida Department of Highway Safety and Motor Vehicles said Tuesday that troopers were working around the clock to escort fuel trucks to gas stations.

L.L. Kirchner, her husband and their dog were among the thousands of residents who joined a slow snake of taillights leaving St. Petersburg on Monday. It took the couple seven hours to reach a hotel in Gainesville, 150 miles away.

“Having seen how close the surge came with Helene, we know it will breach our house if it’s 5 feet higher,” said Kirchner, who lives in a 1920s home a short walk from Tampa Bay.

A satellite image shows Hurricane Milton progressing before its expected landfall in Florida, in the Gulf of Mexico October 8, 2024. CIRA/NOAA/Handout via REUTERS THIS IMAGE HAS BEEN SUPPLIED BY A THIRD PARTY./File Photo

Back-to-back hurricanes

The forecasts are especially precarious for those living in areas still recovering from Hurricane Helene. That hurricane dumped more than 6 feet of storm surge along Tampa Bay’s coastline. Milton is poised to bring double that amount to the same area.

In St. Petersburg, piles of waterlogged furniture and tree limbs still line many streets. Florida officials said they have been working to clear debris from Helene to avoid it becoming projectiles in Milton’s wind.

Jeff Hicks boards up his business ahead of the arrival of Hurricane Milton in downtown Tampa, Florida., U.S., October 8, 2024. REUTERS/Octavio Jones

Andrew Burkhart, 45, who works in health insurance, said his St. Petersburg home flooded during Helene for the first time since it was built in 1969—and now could face even worse damage from Milton.

Helene filled the one-story ranch with 6 inches of water, totaled his 2021 Dodge Ram and damaged his pool. Burkhart had cleaned out the house, moving out everything salvageable in anticipation of extensive repairs.

“It was probably one of the most exhausting weeks I’ve ever had,” he said.

Florida hunkers down

Tourist attractions such as Walt Disney World, Universal Studios, Tampa’s Busch Gardens and Orlando’s SeaWorld said they would close temporarily. The Florida Aquarium, in Tampa, said it had moved several animals to a safer place.

Tampa International Airport, St. Pete-Clearwater International Airport and Orlando International Airport said they would close temporarily. More than 1,700 flights within, into or out of the U.S. were canceled Wednesday, according to FlightAware.

Several schools, including the University of South Florida and the University of Tampa, have closed temporarily.

The Federal Emergency Management Agency has enough funds to support recovery efforts for both Hurricane Milton and Helene, the White House said Monday. The agency has prepositioned teams in the region ahead of the storm.

About 235,000 commercial real-estate properties, worth about $1.1 trillion, are in Milton’s direct path, according to Moody’s, the ratings firm.

President Biden on Tuesday postponed an international trip so that he could manage the hurricane response from the U.S. The president said he spoke to DeSantis on Monday and told the governor to call directly with any needs the state might have.

Biden urged those under evacuation orders to leave immediately, telling reporters on Tuesday that Milton “could be one of the worst storms in 100 years in Florida.”

“It’s a matter of life and death,” Biden said.

Write to Victoria Albert at victoria.albert@wsj.com