Jane Seymour was a last-minute casting choice for Michaela Quinn, reading the script only a day before pilot production began and starting wardrobe fittings the next day.

In a 2015 NPR interview, Jane Seymour revealed she signed her contract for the show, including a five-year commitment, because her then-husband/business manager had lost all her money and put her $9 million in debt, so she needed any TV project to protect her house and children.

Several original pilot cast members were replaced before the series proper: Henry Sanders replaced Ivory Ocean as Robert E., Orson Bean replaced Guy Boyd as Loren Bray, and Jim Knobeloch replaced Colm Meaney as Jake Slicker.

Larry Sellers's minor Cheyenne character Black Hawk was quietly retooled into Cloud Dancing, Sully's blood brother and a major recurring character who later gained the ability to speak English, though his name was never spoken on-screen in his first appearance.

Erika Flores, who played Colleen Cooper, was replaced by Jessica Bowman midway through season three after she asked for a shorter contract than the standard five years; some fans were vocal in protest, writing to CBS to demand an explanation.

Jane Wyman played Michaela's mother Elizabeth Quinn in season one's third episode, but this turned out to be her final acting role of any kind, as she declined to return for a season two guest appearance having fully retired from acting.

The show was largely filmed at the Western set on Paramount Ranch in Agoura Hills, which fans could visit during filming to watch episodes being shot and meet cast members; the set was destroyed in the Woolsey Fire in late 2018.

Other filming locations included the back lot at Universal Studios in Hollywood, where the New England street doubled as the Quinn family home and the New York streets doubled as Boston and Washington.

During season four, Jane Seymour's real-life pregnancy was written into the show, and the following season depicted the birth of Michaela and Sully's daughter, Katie.

CBS ordered a darker tone for season six after realizing the show's demographics skewed toward women 40 and older rather than the coveted 18-to-49 demographic, leading to storylines like a painful miscarriage and Michaela developing PTSD after being shot.

The show's sudden cancellation in 1998 caused a fan uproar compared to the reaction following Star Trek's cancellation in the 1960s, prompting CBS to produce follow-up TV movies instead of a new season.

For the 1999 TV movie Dr. Quinn: Revolutions, both Jessica Bowman and Chad Allen declined to appear due to its content, and composer William Olvis's entire score was scrapped for cheaper music, with the film lacking the series' usual main title sequence or theme.

For the second TV movie, Dr. Quinn: The Heart Within, CBS required it be filmed in Canada (using Old Montreal locations to depict Boston) to save money and limited involvement to only the principal cast; Chad Allen declined to appear after learning none of his original supporting costars were invited.

In 1996, British comedy duo French and Saunders spoofed the series in a sketch titled 'Dr. Quimn, Mad Woman,' with Jennifer Saunders parodying Jane Seymour's role.

In 2014, Jane Seymour, Joe Lando, Orson Bean and other original cast members reprised their roles for a Funny or Die parody titled 'Dr. Quinn Morphine Woman.'

Creator Beth Sullivan said she knew nothing of real historical female doctors when developing the show; CBS asked her for a family drama for the 8pm slot, she proposed a female lead in a period piece, and the character of Michaela Quinn came from her own imagination and interest in the post-Civil War period.