Metal drums filled with chemicals have been thrown into the air from deep within the blaze, posing a danger to the 180 firefighters racing to bring it under control.
A chemical explosion sparked the fire at the factory in Derrimut, west of the CBD, about 11.20am on Wednesday.
No injuries have been reported and it is believed the chemical factory was evacuated safely, Victoria Police said.
Hazardous material and unknown toxins are burning, Fire Rescue Victoria says with the Western Freeway closed near the area for health reasons.
"We don't know what's in that smoke, smoke is toxic and will cause damage," firefighter Michelle Cowling told reporters at the scene.
The blaze was Melbourne's most significant in several years, was not yet under control and would likely burn for days, she said.
"We've got embers burning, fire burning, until we can get close enough even with our aerial appliances that are on site and specialist hazmat people on site we can't get in close enough to cool this fire down," she said.
Those in nearby factories have been evacuated and thousands of people in the area told to stay indoors.
A watch and act alert is current for residents and workers in Albion, Braybrook, Brooklyn, Derrimut, Laverton North, Sunshine, Sunshine West, Tottenham and Truganina.
"Wind is blowing toxic smoke towards the east across Derrimut," the alert stated.
"Anyone located in the area affected by smoke should take shelter indoors immediately."
A significant amount of back smoke is visible around Derrimut and Sunshine West, due to a factory fire. Motorists in the area, including the Western Freeway and M80 Ring Road, should keep their ventilation on recirculate and windows up. — VicTraffic (@VicTraffic) #victraffic pic.twitter.com/8G8YJFzAcyJuly 10, 2024
Drivers in the area have been told to keep their windows up to avoid breathing smoke and have been told not to slow down to view the fire.
The factory is located close to a gas pipeline but emergency services have not issued any alerts over the infrastructure.
Paramedics are also on the scene.
One worker died and two were injured in a factory fire on the same Derrimut street in 2023, also sparked by an explosion.
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