All emergency services, including the air ambulance, were sent after the crash on the B4100 near the junction for King's Sutton at around 12.50pm.
One of the drivers was trapped in their vehicle and had to be rescued by firefighters.
They sustained serious injuries and after initial treatment at the scene was then flown to the John Radcliffe Hospital in Oxford.
The second driver had less serious injuries and travelled to the JR by road in the ambulance for further assessment and treatment.
Police closed the road while the casualties were helped and the vehicles were recovered - the road has since fully reopened after initially reopening from Aynho to King's Sutton.