Six fire engines were on site tackling the blaze at a derelict building in Ryton Street after the callout at 4.52am.
The unbranded buildings has been 'severely damaged' by fire and nearby Newcastle Street is still closed.
At the peak of the operation there were 30 firefighters on site, and Incident Commander John Mills tweeted at 7.30am to say crews were still on the scene damping down.
He added that crews "will remain in attendance in Worksop through the morning.
"Newcastle Street in Worksop is closed. Please avoid this area
"A fire investigation will be taking place."
A spokesman fro Nottinghamshire Fire & Rescue said: "We are still damping down and smoke is minimal. Crews have reduced to three fire engines and an aerial ladder platform. Newcastle Street is still closed but we are get it open as soon as possible. Ryton Street is open with traffic controls in place and some delays expects.