The show was preceded by a 1960 pilot called Head of the Family, in which creator Carl Reiner himself played the lead character (then named Robbie Petrie) opposite Barbara Britton as Laura; the pilot flopped when broadcast on CBS's summer anthology series The Comedy Spot.

Producer Sheldon Leonard saw Reiner's failed pilot script and suggested the show could work if the lead role were recast with a different actor, leading Reiner to rework it with Dick Van Dyke as Rob Petrie instead of himself.

Johnny Carson was a finalist for the role of Rob Petrie, but Sheldon Leonard ultimately chose Dick Van Dyke based on his Broadway performance in Bye Bye Birdie.

About 60 actresses auditioned for the role of Laura Petrie before Mary Tyler Moore was cast, and Moore later admitted she had almost skipped the audition entirely.

Morey Amsterdam was recommended for the role of Buddy Sorrell by Rose Marie as soon as she had signed on to the series.

The character of Buddy Sorrell was loosely based on Mel Brooks, while Sally Rogers was loosely based on Selma Diamond and Lucille Kallen, all writers who worked alongside Reiner on Your Show of Shows.

Rob's brother Stacey Petrie was played by Jerry Van Dyke, Dick Van Dyke's real-life brother.

At least four episodes were filmed without a live studio audience, including 'The Bad Old Days' due to complex optical flashback effects, 'The Alan Brady Show Presents' due to elaborate set and costume changes, and 'The Gunslinger', which was shot on location and was actually the last episode filmed.

The episode 'Happy Birthday and Too Many More' was filmed on November 26, 1963, only four days after President Kennedy's assassination.

CBS planned to cancel the show after its first season, but advertiser Procter & Gamble threatened to pull its ads from the network's lucrative daytime lineup, prompting CBS to renew the series in its Wednesday night slot.

Carl Reiner considered switching the series to color as early as season three but dropped the idea when told it would add about $7,000 per episode; decades later, in 2016, several episodes were computer-colorized by West Wing Studios and aired on CBS.

Show co-star Morey Amsterdam wrote actual lyrics for Earle Hagen's instrumental theme song, which Dick Van Dyke revealed publicly during a 2004 TV Land Awards appearance.

The 2021 Disney+ series WandaVision paid homage to the show's famous ottoman-tripping gag in its first episode, and later confirmed that its black-and-white pilot episode was directly modeled on The Dick Van Dyke Show, with the Maximoffs shown watching the episode 'It May Look Like a Walnut'; producers Matt Shakman and Kevin Feige consulted Van Dyke for authenticity.

In the 1999 Family Guy episode 'Holy Crap,' the opening ottoman gag is parodied with Rob Petrie suffering increasingly severe accidents, and a later episode has the FCC censor the words 'Dick' and 'Dyke' from the show's title due to their alternate slang meanings.