Emergency services were called to Riverton-Wallacetown Highway, between Taramoa Rd and Price Rd, about 1.30pm.
A police spokeswoman confirmed a man died at the scene and a woman with critical injuries was taken to Dunedin Hospital by helicopter.
The woman later died in hospital.
Two fire appliances from Invercargill and Wallacetown, a water tanker, at least five police cars, a helicopter and two St John ambulances were at the scene.
Emergency service staff told the Otago Daily Times the crash was between a Fonterra truck and a motorcycle.
A spokeswoman for the dairy company confirmed one of the vehicles involved in the crash belonged to Fonterra.
She said the driver was not injured.
"We are supporting our driver and we are assisting the police with their investigation in any way we can," she said.
The road was closed for several hours while the Serious Crash Unit attended the scene and diversions were in place.
