Shortly before 8am emergency services were called to the accident scene in the southbound lanes of the motorway, around a kilometre south of the Picton Road overpass.

When they arrived they discovered a Holden Astra and Mazda 4WD had collided, the latter jumping the guardrail and ending up on its roof in bushland.

Police said a 49-year-old woman who was driving the Mazda 4WD died at the scene.

The seven-year-old boy and a seven year-old girl travelling in the Mazda were trapped for a short time.

The seven-year-old boy died on arrival at Liverpool Hospital.

The seven-year-old girl was in a critical condition at the Children’s Hospital, Westmead on Tuesday afternoon.

Police vehicles escorted the two ambulances as they took the children to hospital.

The driver of the Holden, a 49-year-old female was trapped in her car and had to be freed from the wreckage by emergency services.

She was taken by NSW Ambulance paramedics to Liverpool Hospital in a critical condition with head and limb injuries.

Police said the next of kin of all parties had been notified by noon on Tuesday.

Police officers from the Crash Investigation Unit were at the scene on Tuesday but at this stage it is unclear how the head-on crash occurred.

The accident site was located where northbound and southbound lanes are separated by a grass median strip planted with trees.

The section of road where the accident occurred has a 110km/h speed limit.

The Hume Motorway was reopened at 12.30pm after earlier being closed to traffic.