The series began with a pilot movie based on the 1972 detective novel Poor, Poor Ophelia by Carolyn Weston, which aired a week before the series debuted. Edward Hume wrote the pilot's teleplay and was credited with developing the series based on Weston's characters.

The pilot movie featured guest stars Robert Wagner, Tom Bosley, and Kim Darby.

Karl Malden mentioned that he had personally wanted producer Quinn Martin to cast Michael Douglas in the series, and the two developed a close mentor-like relationship both on and off screen.

Michael Douglas's real-life mother, Diana Douglas, guest-starred in the season two episode 'Chapel of the Damned'.

The character Sgt. Art Sekulovich, played by Art Passarella in seasons 3-5, was an in-joke referencing Karl Malden's real surname, which was Sekulovich.

Michael Douglas left the show after the second episode of its fifth season following his success as a producer of One Flew Over the Cuckoo's Nest, which won the Academy Award for Best Picture for 1975; his departure was written into the show as his character taking a teaching position at UC Berkeley.

Writer James J. Sweeney won a 1977 Edgar Award from the Mystery Writers of America for his teleplay for the season-four episode 'Requiem for Murder'.

The show's ratings suffered badly in its final season when ABC moved it to compete directly with Barnaby Jones, another Quinn Martin production, causing the two shows to split the audience and The Streets of San Francisco to fall to 52nd of 104 shows for the season.

The series was sponsored by Ford Motor Company, with half of the vehicles shown being new Ford cars; in early episodes, the entire SFPD cruiser fleet consisted of Ford Galaxies, including the brown 1971 Ford Galaxie driven by Stone and Keller.

A reunion TV movie titled Back to the Streets of San Francisco aired on January 27, 1992, featuring Darleen Carr reprising her role as Jeannie Stone, though Michael Douglas did not appear.