The fire broke out on the mezzanine level of the Graybar Building, directly above the train terminal, at about 9:30am local time (2.30pm GMT).
Sprinkler systems have extinguished the fire, according to officials, but the smoke could not be contained and the station has been evacuated as a result.
Around 85 firefighters are believed to be at the scene and images on social media reveal chaotic scenes in central Manhattan.
Three minor injuries have been reported.
Meanwhile, a track fire has been reported in Penn Station, another major New York train terminal.
More to follow…