The crash occurred on the southbound lane just before 6pm, after a car entered the motorway in the wrong lane near Green Island, Senior Sergeant Brian Benn, of Dunedin, said.
''It appears a car heading north entered the southbound lane causing a head-on collision,'' Snr Sgt Benn said.
Three people from one vehicle and one person from the other were taken to Dunedin Hospital, he said.
Police later described their conditions as serious.
The crash was near the scene of a double fatality crash last month.
A diversion was in place through Green Island.