It happened just after 8 a.m. on the 55 Freeway in Orange, according to the California Highway Patrol.
A CHP spokesperson confirmed at a news conference that the boy had passed away at the hospital.
His identity was not disclosed.
The fatal incident, described by the the highway patrol as an isolated road rage confrontation, occurred near West Chapman Avenue.
At the time of the shooting, the victim was sitting in the back seat of a vehicle as his mother was driving a Chevrolet sedan northbound on the 55, according to CHP Officer Florentino Olivera.
The shooter, who remained at large, was said to be driving a white Volkswagen Jetta.
A description of the suspect was not immediately available.
The northbound 55 Freeway was closed at the scene, and video showed a phalanx of officers scouring the pavement for evidence.
The Highway Patrol said the incident was not connected to a recent string of more than 80 reported shootings at vehicles on California freeways since April.
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