The crash happened on Highway 41 between Avenue 12 and Children's Blvd just after 3 am.
The California Highway Patrol says a Honda crossed into the opposite lane, crashing head-on into a Toyota.
A 22-year-old woman who was a passenger in the Honda was killed in the crash.
Both drivers were taken to the hospital with major injuries.
The 30-year-old man who was driving the Honda later died.
Officials do not believe drugs or alcohol were factors in the crash.