The accident, in which an Opel Astra and a VW Polo collided, occurred around 10pm.
Capt Johannes Ramphora, Springs police spokesman, says the driver of the Astra was the only person in that vehicle.
Read: Community helps bury child from Paul Kruger Highway accident
It is believed the driver of the Astra was driving towards Endicott while the driver of the Polo was driving towards Springs when their vehicles collided.
High Care Ambulance paramedic Andries Sethaiso declared the driver of the Astra and two Polo passengers dead on the scene.
Paramedics stabilised the driver of the Polo and the surviving passenger on the scene before transporting them to a nearby hospital.
Read: Photos: Paul Kruger Highway accident claims life of woman
Sethaiso says one of the patients (20) transported to a hospital nearby, died in hospital.
The names of the deceased could not be revealed because their immediate family has not yet been notified.
The ages of the other three deceased are unknown.
Police are investigating a culpable homicide case.