Police said the pedestrian, a 53-year-old man, crossed the street against a red light at Hayes and Stanyan streets at about 5 p.m., prompting a driver to honk at the man.
In response, the pedestrian slammed his backpack down on the hood of the driver's vehicle, and the driver got out and punched him, police said.
The punch caused the pedestrian to fall and hit his head on the pavement, resulting in serious injury, police said.
The male suspect then drove off, traveling north on Stanyan Street toward Fulton Street, police Sgt. Wilfred Williams said. No arrest has yet been made.