The Donna Reed Show was the first television family sitcom to place the mother at the center of the story, portraying Donna Stone as a strong, active woman rather than a purely domestic figure.

The series was produced by Todon, a company owned by Donna Reed and her husband Tony Owen, who had previously produced several films in Britain.

According to friends and family of Donna Reed, she closely resembled her on-screen character Donna Stone, suggesting the role was modeled directly on Reed herself.

After Shelley Fabares left the main cast in season 5 to pursue a film career, Paul Petersen's real-life sister Patty Petersen joined the show as Trisha, an adopted orphan character.

Bob Crane left the series in 1965 to star in Hogan's Heroes; his character Dave Kelsey was subsequently written out but still referenced, while his on-screen wife Midge, played by Ann McCrea, remained until the show's end.

The show reached its highest Nielsen rating, #16, in Season 6, after Shelley Fabares's departure, partly credited to the addition of neighbors Midge and Dave Kelsey, played by Ann McCrea and Bob Crane.

Silent film legend Buster Keaton made a guest appearance as a hospital janitor in the 1958 Christmas episode 'A Very Merry Christmas.'

In real life, guest star Esther Williams and Donna Reed had been close friends since the early 1940s when both were rising MGM contract stars, and Williams later played a friend of Donna's on the show.

Because Shelley Fabares had previously co-starred in the Mickey Mouse Club serial Annette, four of her Annette co-stars—Richard Deacon, Cheryl Holdridge, Doreen Tracey, and Mary Wickes—made guest appearances on The Donna Reed Show.

The show's theme song is referenced in other media, including a snippet heard in the film Pleasantville during a transition to a fictional idyllic 1950s sitcom, and its full use in Major Payne during a fantasy sequence.