Rescue crews initially believed one of the drivers was missing, but several hours later realised the incident only involved six trucks and that all of the drivers had escaped with only a few suffering minor injuries.
Initial inquiries suggested two of the trucks collided as they attempted to enter a roadside rest stop just after 5am near Gunning in the state's Southern Tablelands, NSW Police said.
One of the trucks appears to have collided with the rear of the other vehicle and shunted it into the others that were parked at the rest stop, police said.
One vehicle was carrying eight tonnes of butane cans, resulting in multiple small explosions when fire crews arrived at the scene.
Also fuelling the resulting fire were loads of alcohol, resin, and memory foam being transported in the other trucks.
"Emergency services were confronted with a fairly horrific scene this morning," Hume Police District Inspector Vlad Mijok told reporters on Tuesday.
All six trucks were destroyed but the male drivers were treated only for minor injuries.
Insp Mijok described the escape as "nothing short of a miracle".
Two of those drivers were taken to Goulburn Hospital for mandatory testing.
Fire and Rescue NSW deployed seven fire trucks, including two Hazardous Materials vehicles and up to 40 firefighters, to the scene.
The Hume Highway remained closed in both directions for several hours.
Police said it may take some time to reopen the road given the extent of debris and potentially hazardous materials left in the wake of the crash.
A crime scene was established and the Crash Investigation Unit enlisted to help with investigations.
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