Four people - a male, female and a 5-year-old boy from one family, and the elderly woman from the other car - were taken to Dunedin Hospital by ambulance with serious injuries.
The boy was in intensive care last night while the adults suffered broken bones.
Southern District Command Centre deployment co-ordinator Senior Sergeant Brian Benn said it was believed the woman had driven from Balclutha yesterday.
The people in the other car, were a family from Mosgiel.
Police closed the southbound lanes of the motorway, diverting traffic into Green Island. Northbound traffic was not affected.
Dunedin man Jonathan Kemp was driving to Green Island to pick up his son when he saw the vehicle heading the wrong way on to the southbound lane of the motorway.
He saw the driver ahead of him make a phone call so continued on, but coming back along the motorway was shocked to discover there had been a crash.
Other drivers last night commented on the Otago Daily Times' Facebook page how they had seen the driver going the wrong way.
Robert Allum said he was on his way home when he saw the car going slowly and he flashed his lights at it.
''I felt absolutely sick when I saw the ambulance go over Saddle Hill.''
The accident occurred just metres away from where a brother and sister were killed last month in a single-car crash.
