Series creator Nat Hiken had previously produced The Phil Silvers Show (Sgt. Bilko), a military comedy, and recruited many of its alumni for Car 54, Where Are You?, including Joe E. Ross, Fred Gwynne, and Beatrice Pons, who reprised her role as Ross's wife.

Several supporting actors, such as Molly Picon, Larry Storch, Gene Baylos, and Carl Ballantine, were so well received in their guest roles that they were brought back for additional episodes.

Interior scenes were filmed at Biograph Studios in the Bronx, while exterior shots of the precinct building were filmed outside the same studio building, located within the territory of New York's real 48th Precinct.

To avoid being mistaken for real police cars during location filming, the show's patrol cars were painted dark red and white, colors that photographed as the correct gray tones on orthochromatic black-and-white film to replicate the NYPD's actual black, green, and white color scheme of the era.

Three different cars served as the title vehicle over the course of the series: a 1961 Plymouth Belvedere for most of the first season, followed by a 1962 and then a 1963 Plymouth Savoy.

The theme song's lyrics, written by Nat Hiken with music by John Strauss, include the line "Khrushchev's due at Idlewild," referencing Soviet leader Nikita Khrushchev's actual 1960 flight to New York's Idlewild Airport to attend the United Nations General Assembly.

Nat Hiken won the Primetime Emmy Award for Outstanding Directorial Achievement in Comedy for his work on the series, out of four total Emmy nominations the show received.

A 1994 film adaptation, shot mainly in Toronto and starring John C. McGinley, David Johansen, and Rosie O'Donnell, was actually completed in 1990 but its release was delayed until 1994 due to the bankruptcy of Orion Pictures; it underperformed both critically and commercially.

In the 1966 film Munster, Go Home!, Herman Munster, also played by Fred Gwynne, calls out "Car 54, where are you?" as a nod to Gwynne's earlier role in the series.

The show's theme song was later parodied as "Mario, Where Are You?" in an Atari commercial for Mario Bros.