The collision happened shortly before 11 a.m. The man was walking west across Sunset Boulevard near Yorba Street when he was hit by a southbound Toyota Corolla, police Officer Albie Esparza said.
The man went through the car's windshield and was pronounced dead at the scene.
Three women who were inside the car were injured and were taken to a hospital. Their injuries are not considered life-threatening, Esparza said.
Sunset Boulevard was still cordoned off midday as police continued to investigate the collision. The front of the red Toyota was covered with a yellow tarp.
There is a crosswalk at that intersection that has blinking yellow lights to alert drivers of the presence of pedestrians, but Esparza said he did not know whether the man was walking in the crosswalk when he was hit.
There was a pair of smashed eyeglasses in the street just south of the crosswalk. Police said they don't yet know if those glasses belonged to the pedestrian.
There are bus stops on either side of Sunset Boulevard at that spot.
The deadly collision occurred as a San Francisco Municipal Transportation Agency meeting on pedestrian and bicyclist safety was under way in another part of town.
Dick Morton and his daughter Ailin live nearby and said Sunset Boulevard is dangerous for pedestrians because of the lack of traffic lights at each intersection.
"People can pick up quite a bit of speed," Dick Morton said.
He said city officials put up the pedestrian warning lights at Yorba Street in the past couple of years but that it still wasn't safe.
"You better be wide awake and fleet of foot," he said.
Chrissy Newsom was among those who gathered on the nearby Sloat Boulevard overpass after the collision to watch the police activity.
Newsom takes care of her grand-aunt, who lives nearby, and said the pedestrian-crossing lights on the Yorba crosswalk don't always get drivers to stop for pedestrians, prompting many to just cross at the overpass.
"It's horrible," she said.