It happened just after midnight on Friday along Highway 198 east of Eggers Drive, near Three Rivers.
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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.
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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.