Emergency services were called to a rest area southbound on the Hume Highway, following reports a b-double crashed into several parked cars shortly after 3pm.

An eight-year-old young girl died at the scene.

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At least four people were also injured and treated at the scene by NSW Ambulance paramedics before being taken to Liverpool Hospital.

A 56-year-old man was treated for a head injury and was transported to hospital in a stable condition while a 55-year-old female was treated for a serious head and leg injury and was transported in a serious condition.

A 40-year-old woman was treated for a leg injury and transported in a stable condition while a a 46-year-old man was treated for a head injury and transported in a stable condition.

Ambulance NSW duty operations manager David Kynaston said five crews, three specialist medical teams' along with two inspectors were dispatched to the scene.

"Arriving at this scene was unlike anything we have experienced as paramedics - it was absolutely horrendous," he said.

"This is incredibly hard for the emergency services and the families involved who have to face the loss and injury of their loved ones.

"It's extremely difficult for paramedics and other emergency services to be confronted with such carnage - it was a very traumatic scene with obviously a lot of chaos."

The male truck driver was not injured and will be taken to hospital for mandatory testing.

Officers from Camden Police Area Command attended and established a crime scene, which will be examined by specialist police from the Metropolitan Crash Investigation Unit.

Motorists are facing significant delays on the Hume Motorway due to the crash.

All southbound and northbound lanes of the motorway are open but the Partridge VC Rest Area is closed.

There will be intermittent closures of one southbound lane of the motorway for investigations into the crash.

Traffic travelling in both directions on the motorway is very heavy, with southbound traffic queued from Narellan Road while northbound traffic is queued from Picton Road.

Motorists are advised to allow for the extra time and exercise caution on the roads.

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