A witness has described to the Herald seeing a vehicle driving down the wrong side of the motorway shortly before the crash.
Wellington road policing manager Inspector Wade Jennings said: "We are currently working to understand the full chain of events that led to this crash.
"This will including speaking to witnesses and reviewing CCTV."
Police are asking anyone who has information that may help in their investigation to contact them immediately.
Emergency services were called to the scene of the two-vehicle collision on the motorway, heading northbound, on the flyover between Molesworth St and the Aotea on-ramp.
Police were told about the incident about 4.20am.
By 8am the motorway had reopened, but Waka Kotahi NZ Transport Agency advised there were speed restrictions in place for both northbound and southbound traffic. Motorists should expect delays, the agency said.
A woman driving to work told the Herald she saw a car driving on the wrong side of the motorway.
"My co-worker was also coming to work at this time and saw far more than me - [he] was trying to signal the driver to turn around."
The woman said her colleague had seen the car get onto the motorway via the Petone entrance before it "sped off".
Desperate attempt to alert drivers
"[My colleague] was trying to alert oncoming drivers by flashing high beams and hazard lights."
The woman got off the motorway at the Aotea off-ramp and did not see another vehicle.
"The crash seems to have happened just after that," she said.
"It would've been just before 4.30am as that is when I started work."
The woman said her colleague suspected there was a possibility the driver going down the wrong side of the motorway had become confused about where they were going.
Police said two people were travelling in each vehicle involved.
A Wellington Free Ambulance spokesperson said the two people with injuries were in a critical condition.
Police alerted the public via its Facebook page just after 5am - telling people to avoid the area completely.
"Police are requesting people leaving Wellington avoid using the motorway or delay their travel."
People driving southbound into Wellington are also asked to "travel with care" particularly as they go past the crash site, and could also expect delays.