It happened just after midnight on Friday along Highway 198 east of Eggers Drive, near Three Rivers.
CHP officers say the 22-year-old driver of a Dodge Neon drifted off the highway and slammed into a roadway sign and tree before falling down an embankment.
The driver, a 24-year-old woman in the passenger seat and two children, ages three and six, were all rushed to Kaweah Health Medical Center in Visalia.
Authorities say the six-year-old boy died from his injuries at the hospital.
Officers are working to determine what caused the driver to veer off the highway. It's unclear if drugs or alcohol were factors in the crash.