It happened around 4:30 p.m. on eastbound Highway 92 at Canada Road west of Interstate 280, CHP Redwood City said.
Officials say a gray BMW was traveling westbound on SR-92 when for "unknown reasons," a red Honda Accord that was traveling eastbound veered into the westbound lane - crashing head-on with the BMW.
The driver of the BMW, identified as a man in his 30s, was pronounced dead at the scene, according to CHP. The driver of the Honda, a woman in her 20s, suffered major injuries and was rushed to Stanford Medical Center.
Authorities say it is unknown if DUI is a factor in this crash.
California Highway Patrol and the San Mateo County Sheriff's Office are on scene.
CHP estimates Highway 92 will be closed in both directions for about two hours. The public is asked to please avoid the area and use alternative routes.
Take the Bunker Hill exit, go west and head south to SR-92, CHP advises. You can take SR-92 to Half Moon Bay.