The series revolves around former San Francisco Police Department (SFPD) Chief of Detectives Robert T. Ironside (Raymond Burr), a Navy veteran, widower, and veteran of 25 years of police service, forced to retire from the department after a sniper's bullet to the spine paralyzed him from the waist down, resulting in his reliance on a wheelchair.

In the pilot episode, a television movie, Ironside shows his strength of character and gets himself appointed a peculiar and unprecedented job; a "special department consultant", by his good friend, Police Commissioner Dennis Randall.

In addition, delinquent-turned assistant Mark Sanger (Don Mitchell), who subsequently attends and graduates from law school (night classes were mentioned from early on), joins the San Francisco police force himself in the sixth season, then marries late in the run of the series.

After the program's fourth season, Anderson left for personal reasons, and her character was then replaced by another young policewoman, Fran Belding (Elizabeth Baur), who filled much the same role for four more years.

Ironside uses a fourth-floor room (for living and office space) in the old San Francisco Hall of Justice building, which housed the city's police headquarters.

This is replaced in the episode titled "Poole's Paradise" after the van is destroyed by Sergeant Brown as part of a plan to trick a corrupt sheriff.

At the end of the episode, the patrol wagon is replaced by a one-off fully custom modified 1969 one-ton Ford Econoline Window Van.

The shows contained stock footage of San Francisco, with pan shots of Coit Tower or clips of traffic scenes.

The iconic theme music has since been sampled in numerous recordings and soundtracks to television commercials and shows, including Kill Bill: Volume 1.

At the time the Ironside reunion went into production, Burr had been suffering from kidney cancer that had metastasized to his liver, and the disease left him unable to stand or walk without assistance.

Unlike the original series, which took place in San Francisco, the reunion was set and filmed in Denver, Colorado, with the justification that the character Ed Brown had become the city's deputy chief of police.

"The Over-the-Hill Blues" (1974) At the start of its sixth season, Ironside did a two-part crossover episode with The Bold Ones: The New Doctors, titled "Five Days in the Death of Sergeant Brown", where Ed is critically injured by a sniper and is treated by Dr. David Craig and his medical staff.

Part two features a longer edited version of Quincy Jones' "Ironside" theme as heard on his 1971 album Smackwater Jack.

NBC's 1971 fall TV season opened with a two-hour crossover between Ironside and a new series, Sarge, starring George Kennedy as a cop-turned-priest.

Jessica Walter guest-starred in a spin-off episode for the series Amy Prentiss, which aired as part of The NBC Mystery Movie during the 1974–1975 season.

The 22nd episode of season seven, airing in March 1974, and titled "Riddle at 24,000," was a pilot for "Dr. Domingo," a proposed spin-off series starring Desi Arnaz as a crime-solving physician in a small, California town.

Actor Blair Underwood took on the title role (with none of the other characters from the original series being used), while the action was relocated from San Francisco to New York City.

Impressionist Billy Howard included Ironside as one of the detectives parodied in his novelty hit record "King of the Cops."

American Dad has an episode, "Wheels and Legman," that loosely parodies Ironside and similar programs in which Roger and Steve have a fictional detective agency.

In the "Gone Efficient" episode of Harvey Birdman, Attorney at Law, a man in a wheelchair is shown pleading a case in front of Judge Mentok (who strongly resembles Raymond Burr) as a nod to both Ironside and Perry Mason.

A promo for the adult animated sitcom Archer was made in the style of the show's opening sequence, replacing Ironside with the character Ray Gillette, who had been temporary confined to a wheelchair after a spinal injury.