Police say seven people had to be taken to hospital after the crash on the Hume Motorway about 2.15pm (AEDT) on Tuesday.
An occupant of the truck died at the scene.
Fifteen people from the cars involved were interviewed.
All southbound lanes of the highway were closed between Narellan Road and Campbelltown Road, and were expected to remain closed for "an extended period," police said.
Two of three closed northbound lanes were expected be reopened after 4.30pm.
Southbound traffic was queued back more than 10 kilometres to Brooks Road, while northbound traffic was queued more than five kilometres back to Menangle Road.
Motorists were advised to avoid the area.
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