NYPD Blue was created by Steven Bochco and David Milch, drawing inspiration from Milch's relationship with Bill Clark, a former NYPD member who later became one of the show's producers.

The show was originally conceived as a vehicle for David Caruso's character John Kelly, with promotional shots placing him in the foreground; after Caruso departed in season two, the series shifted to an ensemble format built around Dennis Franz's Andy Sipowicz.

Two actresses were initially cast as young Latina detectives intended to become regulars; one left during pre-filming over creative differences, and Vanessa Marcil appeared as a one-episode guest in the season 9 premiere before producers decided against making her a regular and continued casting until hiring Jacqueline Obradors.

Although the series was set in New York City, filming primarily took place in the greater Los Angeles area, with only exterior shots using actual New York landmarks; in the final season, production moved entirely to Los Angeles to save money.

Exterior shots of the fictional 15th Precinct used the real 9th Precinct building on East 5th Street in New York City, a location also used for the series Kojak.

The show's instrumental theme, composed by Mike Post, remained unchanged throughout the series and opens with a percussion arrangement evoking a New York City subway train departing a station, followed by an oboe melody influenced by Irish-American music used at NYPD ceremonies.

The series' depictions of nudity and raw language led at least 30 ABC affiliates, mostly in smaller conservative Southern markets, to refuse to air it at launch, though 29 eventually began broadcasting it once ratings overruled their objections.

In 2005, activist L. Brent Bozell III said the show's nudity motivated him to found the Parents Television Council, and in 2008 the FCC fined ABC $1.4 million over the episode 'Nude Awakening' for scenes of adult sexual nudity, though the fine was later rejected by a federal appeals court in 2011.

Co-creator David Milch was known for a controversial working style involving procrastination and last-minute on-set script changes, which contributed to a difficult environment and reportedly influenced Jimmy Smits' and Andrea Thompson's decisions to leave the show; Milch himself cited his own alcoholism and addictions as contributing factors.