The police serious crash unit is investigating both deaths.
More crashes were also reported around the region.
A Fire and Emergency New Zealand (Fenz) spokesman said crews from Edendale, Mataura and Gore were called to a three-car collision at the intersection of Main St (SH1) and Glendau St, Mataura, about 10.20am on Saturday.
St John sent a manager, who treated seven patients at the scene. Two had moderate injuries and five minor injuries.
Yesterday, four people were treated for minor injuries at the scene of a St Bathans Loop Rd crash at 12.40am.
Fire crews from Omakau and Ranfurly stations attended, while St John sent two first response units and a Prime doctor.
A single-vehicle crash happened in the Waihola Highway (SH1) about 1.25am on Saturday.
Fenz crews from Milton attended and a person with moderate injuries was taken to Dunedin Hospital by ambulance.
Fire appliances from Wallacetown and Kingswell attended a crash in the Wallacetown-Lorneville Rd Southland about 12.45am yesterday.
An ambulance was sent but was stood down before it arrived.