It happened just after 11 pm Sunday on Highway 59 south of Washington Road, west of Chowchilla.
The California Highway Patrol says a 30-year-old man was driving northbound in a 2016 Toyota Camry, and a 28-year-old woman was driving southbound in a 2022 Camry.
They say the woman drove into the northbound lanes and collided head-on with the man's vehicle.
It's not known why she veered into the northbound lanes.
Both drivers were pronounced dead at the scene.
It is not known if drugs or alcohol played a role in the crash.