Police said the crash happened in Old Coach Rd between Kaiwera Downs Rd and Isla Rd, on State Highway 93 about 6am today.
A Hato Hone St John spokesman said it was notified of the crash at 5.55am and responded with two ambulances, two helicopters, one rapid response unit and one operations manager attended.
Two patients were seriously hurt and flown to Dunedin, while another patient was in a moderate condition and transported to Invercargill Hospital by road, he said.
SH93 was closed between the intersections of SH1 Mataura and SH1 Clinton for most of the morning, with a detour via SH1 in place.
The New Zealand Transport Agency advised about 10.50am that the highway had reopened.
However, people were still asked to drive with care on the section of road between Clinton and Mataura.
