Fire and police crews are at the scene of the huge inferno in White Lea Road, Swinton.
South Yorkshire Fire and Rescue has said it has a number of appliances at the scene of the incident.
A South Yorkshire Police spokesman said: “Our officers are currently assisting South Yorkshire Fire and Rescue with traffic management while they tackle a fire at a premises on White Lea Road, Swinton.
“Please avoid if possible. And it is advised local residents keep doors and windows closed until the fire is out due to toxic smoke in the air.
“Currently, the whole of White Lea Road from the junction with Wath Road in Mexborough to Rowms Lane in Swinton is closed, as is Marriott Road in Swinton.
A spokesman for South Yorkshire Fire and Rescue said: “We currently have five fire engines in attendance at a large industrial fire on White Lea Road, Mexborough.
“If you live nearby, please ensure that you close all windows and doors as there is a large amount of smoke in the area.”
Nearby residents have said the blaze is near to the popular Avago indoor karting centre, but it is understood the venue has not been impacted by the blaze.
The site of the fire is near to Swinton railway station and the main Doncaster- Sheffield railway line but services are not thought to have been affected at this stage.