The crash happened around 6:40 am. on 6th Avenue and Clinton Avenue, southwest of Kingsburg.
California Highway Patrol officers say a Toyota Tundra and Jeep Cherokee collided after one of the vehicles crossed into the opposite lane.
The man driving the Jeep suffered major injuries and was airlifted to a hospital for treatment.
Officials say the driver of the Tundra had moderate injuries and was also taken to a hospital by an ambulance.
CHP officers are investigating to determine which car crossed the center line. Traffic in the area is blocked as authorities continue their investigation.