Eight fire engines are putting out the blaze on Oldham Road in Miles Platting.
The building on fire is thought to be a commercial premises.
Images from the scene depict the fire opposite the Shell Garage near Queens Road.
Residents have been warned to avoid the area while the firefighters are working.
People living in the area are urged to keep their windows and doors shut.
Transport for Greater Manchester have closed School Hill road as well as stopping rail services between Hebden Bridge and Manchester Victoria.
Northern Railway warns there will likely be “widespread disruption” due to the fire.
Residents have taken to Twitter to express their shock, reporting sightings of the smoke from miles away.
“We can see the smoke from Moston,” a Twitter user wrote.
“I can see it from two miles away!” another wrote.
“Looks like a big one! Hope everyone is alright,” a third chimed in.
“Multiple fire crews rushing in from all over the city. Can’t believe it’s got so big so quick,” another Tweet read.