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 closed School Hill road as well as stopping rail services between Hebden Bridge and Manchester Victoria.
While rail services have since been reopened, National Rail has confirmed that residents should expect disruptions.
“Many of our trains are displaced as a result of the line closure and may not be in the correct place to operate services in the morning,” a spokesperson said.
“Disruption is possible on all routes in and around Manchester, but we’ll be working through the night to provide the best service possible.”
Road closures are still in place.
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 said.
“Multiple fire crews rushing in from all over the city. Can’t believe it’s got so big so quick,” another Tweet read.
“Our @manchesterfire crews are working hard at scene of a building fire, Oldham Rd, Manchester. Please avoid area. Road closures in place,” a Twitter user wrote.