The California Highway Patrol says the crash happened on Interstate 5 at the Fresno/Coalinga off-ramp.
Two vehicles collided along the interstate, and one of the cars caught fire and exploded.
Three people inside one of the vehicles were killed, the Fresno County Coroner's Office said. Their identities have not been released.
Officers are working to determine what led up to the crash.
Interstate 5 was closed for several hours while officers investigated but it has since reopened.