One of the trucks burst into flames following the smash at Miranda, south of Port Augusta, about 1am Friday.
Emergency services were at the scene, about 5km south of Horrocks Pass Rd.
Major Crash investigators were on their way to the location.
The Augusta Highway was closed in both directions and drivers were being diverted through Wilmington.
Police asked motorists to avoid the area if possible and to check traffic.sa.gov.au for the latest road closure updates.