The fertiliser truck tipped on its side at 9.40am, blocking State Highway 1 about 4km north of Balclutha for several hours.
Acting Sergeant Craig Dinnissen, of Balclutha, said two cars, a van, and a truck-and-trailer unit were involved.
It appeared there was an initial crash at the scene, when one of the cars skidded out of control and crashed on the left-hand side of the road.
Police said the driver of the Toyota van, believed to be travelling in the opposite direction, towards Milton, appeared to have seen the crash and completed a U-turn to offer help. The van parked near the crashed car with its hazard lights on but when the truck came around the 75kmh corner, locked up and jackknifed.
The male driver, believed to be in his 40s, was airlifted to Dunedin Hospital, and is believed to be suffering a broken left arm, and possible back injuries.
One driver was taken to Clutha Health First by ambulance with minor injuries, and was discharged shortly after.
The others were treated at the scene. None of the vehicles were carrying passengers.
Otago Regional Council staff worked with firefighters to clear the fertiliser and spilt fuel from the road. Traffic was backed up 2km on either side of the crash and was diverted along a nearby road.
Police and the Serious Crash Investigation Unit are investigating.
