The tractor-trailer plowed through a guardrail while heading east on Highway 401 Tuesday, plunging into the river west of the town, police say.
The eastbound lanes of the country's busiest highway were closed between Cambridge and Woodstock for 11 hours as police and firefighters tried to find the occupants.
The crash happened shortly after 11:30 a.m. The truck was travelling from Chicago to Mississauga.
Police hope an autopsy of the driver may shed light on what caused the crash.