The accident created a spectacular fireball, witnesses said, and the flames were still not under control hours later in Lac Megantic, around 250 kilometers east of Montreal.
Witnesses reported as many as six large explosions during the night.
Some 120 firefighters were battling the blaze, including some who came across the border from the US state of Maine, just 25 kilometers south of the town.
Several buildings in the center of town were engulfed in flames.
Also Read
Rescue workers at a morning press conference said they were not immediately able to determine a human toll from the accident.
The provincial police of Quebec said they were unable to determine if the missing people had been in town overnight, but several witnesses said they were unable to reach relatives who lived near the accident site.
Meanwhile, the crude oil, which was headed for the US coast, gushed through streets like a river, and the extent of the environmental damage was not immediately clear.