A St John ambulance spokeswoman said two people were transported to Dunedin Hospital, one with serious to moderate injuries and the other with moderate injuries, after emergency services were alerted at 5.11pm.
Their injuries were not believed to be life-threatening.
One large brown car, with frontal damage, had come to rest across the highway, blocking both lanes, after the apparent head-on crash.
And another smaller, grey car, with frontal and windscreen damage, came to rest in a ditch off the highway, having careered through or over a flexible wire safety barrier.
Within four minutes of the arrival of the Willowbank fire appliance, which carries specialist cutting gear, firefighters realised people were trapped in the two cars and they called in the Lookout Point appliance, which also carries cutting gear.
About six appliances from Dunedin attended the crash, which happened in wet conditions. A mobile crane was later brought in to retrieve the smaller vehicle from the crash site near the motorway summit on the Dunedin side.
Fire communications centre shift manager Brent Dunn confirmed it had been a "significant rescue incident", and a "great example" of effective collaboration between fire, police and St John in a potentially ‘‘very dangerous’’ situation.
A firefighter had stepped in and driven one of the ambulances back to Dunedin, probably to enable an ambulance officer to provide further help for the patients, he said.
Traffic on the Northern Motorway was disrupted for more than two hours after police sealed it off in both directions to protect the crash scene. Local diversions were put in place, including southbound traffic being diverted over the unsealed Leith Valley Rd.
Police issued a statement at 7.46pm confirming the highway had been reopened and thanking motorists for their patience.
