Rock Hudson originally did not like the series, but agreed to make it because of the bad films he was being offered. He said, "Television is the monster of all time that eats everything and everybody. When they wanted McMillan & Wife to go to two hours I said, 'Why? The thing doesn't even hold up for ninety minutes!'." However after the series ended he saw an episode repeated on television and admitted, "It was better than I thought. Why didn't I put more into it?".
Both Susan Saint James and Nancy Walker left the show at the end of the 1975-1976 season. Saint James because of a contract dispute, and Walker because she had just signed a contract with ABC.
Part of the original "Sunday NBC Mystery Movie" which rotated with the series McCloud (1970) and Columbo (1971).
In Seasons 1-4, the McMillan residence is a townhouse in the middle of downtown San Francisco. Several episodes and segments open with establishing shots of the outside of the flat. At the beginning of Season 5, shots of the outside of the McMillan home is an actual stand alone house; yet the interior remains the same. There is no explanation in the series as to the extremely obvious change.
The series was inspired by the "Thin Man" series of films starring William Powell as a former private detective and Myrna Loy as his wife, who talks him into taking cases and tries to participate in the investigations.