The incident happened at about 3:45 p.m., when the truck lost control on the curve going from Highway 640 to Highway 40, east of Montreal.
Both highways have been re-opened to traffic.
The explosion sent up thick black plumes of smoke, which could be seen for kilometres.
The driver of the truck was killed. Two other people suffered minor injuries.
'The whole highway was on fire'
Angelo Romano lives across from the highway. He said he heard and felt the explosion from inside his condo.
"I hear a big bang, so I didn't really pay attention, but the second bang I felt the building shake," he said.
"The whole highway was on fire, it was incredible to see."
Police investigate cause
Firefighters were finally able to approach the fire and control the flames about an hour after the incident.
Sûreté du Québec Sgt. Gregory Gomez del Prado said it's not clear what caused the truck to lose control.
"It's still under investigation. We're trying to determine — was it speeding, was it something else?" he said.
Gomez del Prado said a van was also involved in the incident.
Investigators are still trying to find out more about the contents of the tanker truck, but Gomez del Prado said they do know that it was some sort of flammable liquid.