Seven trucks were destroyed in the crash. Photo: Fire and Rescue NSW

The flames of a fiery crash involving multiple semi-trailers have been extinguished, but a driver remains unaccounted for as emergency crews work to clear a major highway. 

Two trucks appear to have collided and careered into five other rigs at a roadside rest stop just after 5am near Gunning, in the state's Southern Tablelands, according to Fire and Rescue NSW.

One truck 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.

All seven trucks were destroyed.

Most of the drivers managed to escape the wreckage but one hadn't been located, according to Fire and Rescue NSW.

NSW Ambulance responded to the crash and treated six drivers for minor injuries, according to NSW Police.

Two of those drivers were taken to Goulburn Hospital for mandatory testing, police said.

Fire and Rescue NSW has 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 as of 11am (local time).

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 had been established and the Crash Investigation Unit will assist with investigations.