The shooting happened shortly before 1 a.m. Tuesday on the northbound lanes of the freeway near the Florence Avenue off-ramp, according to the California Highway Patrol.
Authorities say the driver of a black sedan fired an unknown number of shots at the victim's car. A motive for the shooting has not been determined.
The victim, who has not been identified, managed to pull over and call 911. He was taken to St. Francis Hospital but did not survive his injuries.
The suspect fled the scene and authorities are asking anyone with information to contact officers at 323-980-4600.