The episodes often found Mac and Sally attending fashionable parties and charity benefits before solving robberies and murders.

Charles Enright and Nancy Walker as Mildred, the couple's sarcastic, hard-drinking maid, provided comic relief.

After its network run on NBC, it appeared regularly as part of The CBS Late Movie and later, in the form of syndicated reruns on local and cable television in the United States.

Mildred, meanwhile, was written out as having left the McMillans to open her own diner on the East Coast, which was an inside joke playing up her role as Rosie the waitress in a then-ongoing series of commercials for Bounty paper towels.

John Schuck had his role reduced as he joined the sitcom Holmes & Yoyo which was produced by Leonard B. Stern.

Meanwhile, Sergeant Enright was promoted to Lieutenant and became Deputy Chief of the San Francisco Police, which took him away from his position as Mac's liaison.

On May 21, 2010, Visual Entertainment announced it had acquired the rights to distribute McMillan & Wife on DVD in Region 1.

On November 20, 2013, it released McMillan and Wife: The Complete Collection, a 19-disc set featuring all 40 episodes of the series.