The cyclone was upgraded by the Bureau of Meteorology on Thursday morning and is now 290km north of Port Hedland.
Mayor Peter Carter said the system was likely to cross the coast closer to the mining town of about 16,000 people than initially forecast.
"What's happening with this cyclone is very unusual and a lot of people are getting very worried because it's getting closer and closer to Port Hedland," he told AAP.
He said an eerie quiet had descended over town as residents prepared for the impact of the cyclone.
"It's very subdued. There's not a lot of wind (yet) and there's light drizzle and light cloud," he said.
"At the moment it's very quiet but this thing is supposed to hit us in 14 hours (and) that could change again.
"The longer it stays out in the ocean the bigger it's going to get (and) the more powerful it's going to get."
Ilsa is expected to cross the coast near Pardoo Roadhouse, 150km northeast of Port Hedland, in the early hours of Friday.
Wind gusts of up to 275km/h are likely near the cyclone's centre as it tracks inland.
Mr Carter said an evacuation centre had been set up in town for residents who didn't feel safe in their homes.
The town's massive port that exports iron ore around the world has also been emptied of ships.
"Most infrastructure is designed for cyclones. It's the flying debris that we worry about," Mr Carter said.
"Your wheelie bin, your barbecue, your gas bottle ... put it away. No one wants them to become missiles."
Communities from Bidyadanga to Whim Creek, including Port Hedland and inland to Marble Bar, Nullagine and Telfer, have been urged to keep their emergency kits on hand.
Abnormally high tides, destructive winds and up to 400mm of rain are forecast.
The BOM warned the "very destructive" part of Ilsa, with extreme gusts of up to 275 km/h, could impact the area between De Grey and west of Bidyadanga.
Workers and tourists at Eighty Mile Beach caravan park and nearby Wallal Downs cattle station are being evacuated, along with non-critical workers at Newcrest's Telfer mine and BHP's sites across the region.
Extra emergency workers, essential supplies and aircraft have been sent to the area as authorities warn the North West Coastal Highway could close between Port Hedland and Broome due to flooding.
Communities from Beagle Bay to Broome have been given the all-clear but have been asked to watch out for residual damage, including fallen trees and power lines.
Ilsa is forecast to maintain tropical cyclone intensity into Friday as it tracks inland to Telfer and moves east.
The system is expected to weaken below tropical cyclone strength overnight on Friday before moving east into southern parts of the Northern Territory.
It is the first category-four system to strike the region in almost a decade.
The last, named Tropical Cyclone Christine, crossed the coast southwest of Port Hedland in December 2013.
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