The train failed to stop as it sped into Hoboken station, went up over the bumper blocks at the end of the track and rammed into a wall, a New Jersey transit official told AFP at the scene.
Michael Larson, another transit employee, told reporters he heard a "bomb-like explosion" as the train hit the bumpers with such force that it went airborne -- hitting the station's roof and causing it to partly collapse.
Video and photos on social media showed major damage to the transit hub just over the Hudson river from Manhattan, with the train tangled in wires and debris from what appeared to be caved in portions of the roof.
Passengers described the train -- which was carrying around 250 people -- ramming at full speed into the bumper at the end of the track.
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New Jersey Governor Chris Christie confirmed to CNN one fatality from the early morning accident. US media earlier reported that three people had died. No official toll was immediately available.
State transit spokeswoman Jennifer Nelson told reporters at the scene that more than 100 people were injured, with "multiple critical injuries."
All the victims have been evacuated to two local hospitals.
Kenneth Garay, chief medical officer at Jersey City medical center, said its surgeons were "all hands on deck" as they treat patients suffering from orthopedic injuries, internal injuries and lacerations.
Garay said that another 40 people were transported from the train station by bus to be treated for "walking types of injuries."
Governor Christie told CNN there was no longer anyone trapped on board the train, and that the train engineer was among those being treated in hospital for unspecified injuries.