The officers told the man to drop his handgun before opening fire on him, but officials said he did not comply.
"Officers faced with immediate safety concerns for themselves, witnesses at the scene and heavy vehicular traffic at rush hour fired at the suspect," the California Highway Patrol told the San Francisco Chronicle.
The shooting happened late Friday afternoon on Highway 101 in San Mateo, south of San Francisco. It's unclear if the armed man had fired on officers.
Officials have not identified the man.
No other injuries were reported in the shooting that closed northbound traffic on the highway for several hours. The shooting remains under investigation.