A Fire Service spokesman said firefighters from Mosgiel Station and Lookout Point Station were called to the crash in Wickliffe St, near Tudor Lane, about 5.30pm.
The crews cut both doors from the right side of a Ford SUV to remove the driver.
As St John staff put the extricated man on a stretcher and moved him to an ambulance, another man sat in the driver's seat of a crashed Toyota Corolla.
A police spokeswoman said the SUV driver sustained serious injuries and was taken by ambulance to Dunedin Hospital.
The other driver was assessed by ambulance staff at the scene.
The serious crash unit would attend the scene today, she said.