According to the state-run TASS News Agency, the fire erupted in the Nevskaya Manufaktura building, an iconic landmark in the city which dates back to 1841 when it was used to manufacture fabric, at around 12.35 p.m. on Monday.
An emergency service source told TASS said that "when putting out the fire, one firefighter died. Earlier, communication with him was lost".
The source said that a gas and smoke rescue service squad was inspecting the building.
"They were cut off by the fire, two of them are taken to hospital, the third one died," he said, adding that the wounded officers have sustained 40-50 per cent burn injuries.
A representative of the St. Petersburg office of the Russian Emergencies Ministry told TASS that 40 people were evacuated and the building's roofing and floor deck have collapsed.
"All four floors of the building are engulfed in flames, and the roof and floor deck have caved in."
The fire, which has now spread to 10,000 square kilometres, is yet to be put out.
The St. Petersburg prosecutor's office has launched a probe into the incident, the cause of which remains unknown.
The building sits on the bank of the Neva River, which runs through St Petersburg, Russia's second largest city, the BBC reported.
It was run by the government during the Soviet period, then privatised in 1992.
In 2001 the factory was added to St Petersburg's list of historic and culturally valuable sites.