A Fire and Emergency New Zealand spokeswoman said crews from Dunedin and Willowbank stations were called to the crash about 12.20am this morning.
A St John spokesman said one ambulance took the patient to Dunedin Hospital in a critical condition.
Constable Nick Turner, of Dunedin, said a Subaru Forrester was heading south on Castle St with four occupants and T-boned a Holden Barina that was headed east on St Andrew St.
The Barina was driven by a 22-year-old man who was the only occupant, he said.
The people in the Forrester were uninjured and the driver of the Barina had been airlifted to Christchurch Hospital for treatment, Const Turner said.
Initial investigations indicate the Forrester had the right of way, Const Turner said.
The accident comes after a serious crash outside Dunedin Railway Station on Wednesday night which left a 27-year-old man in Dunedin hospital with serious injuries.
A Waka Kotahi New Zealand Transport Agency update said the crash scene at the intersection of Castle St and St Andrew St had been cleared about 6.40am.