The horrific crash occurred early yesterday (Wednesday) morning as the 16-year-old Griffith girl, driving a white Ford sedan unaccompanied by an adult, collided with a southbound vehicle 300 metres south of the Telegraph Point traffic bridge.

The impact of the collision sent the 40-year-old driver of the southbound vehicle careering off the road into a ditch and ripped apart the driver's side of the Ford's bonnet.

Ambulance officers received a call at 6.04am and attended the scene where the female driver was pronounced dead at the scene.

The three passengers in the Ford were conveyed to Port Macquarie Base Hospital with serious injuries.

A 15-year-old girl suffered abdominal and back injuries, while an 18-year-old female sustained neck, leg and head injuries and a 17-year-old girl sustained abdominal and arm injuries.

A 40-year-old male travelling to work at the Herons Creek roadworks was trapped by confinement 100 metres from the other vehicle.

The male sustained serious chest and pelvis pain and was conveyed to Port Macquarie Base Hospital for further treatment.

Two witnesses were treated at the scene for shock.

The accident comes only a day after paramedics reported an increase in fatal accidents on the weekend and urged drivers to slow down.

New South Wales Ambulance Services District Manager for Hastings, Steven Towle called for drivers to take care especially at high-risk times.

"From 3am-6am is the worst time for fatigue and when the most accidents occur," he said.

"Right around sun-up and 10pm at night are the highest risk times for drivers and driving for long periods is dangerous."

The crash closed all lanes of the highway in both directions for almost three hours. The highway re-opened just before 9am.