Stanley Ford is a successful newspaper cartoonist. He enjoys his bachelorhood in his New York City townhouse, with his loyal and attentive valet, Charles Firbank. Stanley's widely syndicated comic strip, Bash Brannigan, is a secret-agent thriller, and Stanley insists Brannigan will not be shown doing anything which Stanley himself has not actually done, which he ensures by enacting storylines, playing Brannigan, while Charles takes photographs which Stanley uses as visual references when drawing the comic strip.

While attending a bachelor party for his friend Tobey Rawlins, Stanley becomes intoxicated and somehow ends up marrying the beautiful Italian woman who appears out of a cake, with an equally drunk judge performing the impromptu wedding. The following morning, Stanley wakes up and, even as he gazes at his naked wife sprawled on the bed, bitterly regrets it. Refusing to work for married couples, Charles storms off to start packing. Stanley's attempt to discuss the situation with his new wife backfires when it emerges that she does not speak English. His lawyer, Harold Lampson, advises him that a divorce is not possible without legal justification.

Stanley's new bride is cheerful, affectionate, sexy and a skilled cook, despite only speaking Italian. To learn English, she spends time with Harold's manipulative, hen-pecking wife Edna, who speaks fluent Italian, but she also learns Edna's manipulative ways. Charles resigns, taking a new job with the jilted Rawlins. Stanley now finds his bathroom filled with beauty products and lingerie, and he is kept awake at night by his wife constantly watching television, which she says helps with her English. She keeps a yapping little dog, her Italian cooking causes his weight to increase, and she announces that her mother will be coming from Rome to live with them.

Working at home, Stanley becomes increasingly irritated by the constant presence of his wife, and he changes his Bash Brannigan newspaper strip from the exploits of a daring secret agent to a domestic household comedy, The Brannigans, but it remains wildly popular. In a bid for some privacy, Stanley calls a meeting of his associates at his all-male health club. When Edna learns of the meeting, she telephones Mrs. Ford and arouses her suspicions about Stanley's activities. Mrs. Ford sneaks into the club to confront her husband, resulting in Stanley being banned for violating its "no women" policy.

Stanley concocts a plot in his comic strip for Brannigan to kill his wife by drugging her and disposing of her body in concrete on the construction site next to his townhouse, so that Brannigan can resume his career as a secret agent. As usual, he enacts the events live before drawing the strip, drugging his wife during a cocktail party, but using a department-store mannequin to play out her burial in the concrete from the mixer.

The next morning, while Stanley is sleeping, Mrs. Ford sees the finished comic strip describing Stanley's murder plan. Heartbroken, she leaves, taking only her dog. After publication of the comic strip in the newspapers, and with Mrs. Ford having disappeared without explanation, Stanley is arrested and charged with murder, with his comic strips used as prosecution evidence at the trial. Facing a possible conviction, Stanley takes up his own defense and pleads justifiable homicide, appealing to the all-male jury's frustrations regarding their own wives and marriages. He is acquitted unanimously, and the men in the courtroom applaud wildly and carry Stanley out on their shoulders.

Accompanied by a joyful Charles, Stanley goes home and sees traces that his wife has returned and is in their bedroom. Charles reminds him that killing her now would not have any legal consequences, since Stanley has been acquitted of her murder and trying him again would constitute double jeopardy. However, when he enters their bedroom, he finds her naked under the covers, and she silently invites him to join her, which he does. Charles enters what used to be his bedroom and finds Mrs. Ford's mother, who has arrived with her daughter and is unpacking. Like Charles, she has a prominent tooth gap, and there is instant chemistry between them. Breaking the fourth wall, Charles closes the door.

• Jack Lemmon won the Golden Laurel for Male Comedy Performance at the Laurel Awards.
• Claire Trevor was nominated for Golden Laurel for Female Supporting Performance.
• Jack Lemmon was also nominated for BAFTA Film Award for Best Foreign Actor.

The music was composed by Neal Hefti.

The film holds a 64% rating on Rotten Tomatoes based on 14 reviews, with an average rating of 6.2 out of ten. Variety stated: “Finesse and desire aren't enough to overcome the fact that Axelrod's script doesn't make the most of its potentially antic situations.” The opinion of Bosley Crowther of The New York Times was: “Never have I seen a movie, serious, comic or otherwise, that so frankly, deliberately and grossly belittled and ridiculed wives” and “this stuff is funny just so long as one can go with the sour joke- -and that depends upon one's tolerance of trivia and also, perhaps, upon whether one is a fellow or a girl".

• The film is referenced in Fawlty Towers in the episode "The Wedding Party". Basil Fawlty says: “Yes, awfully good, I saw it six times”. In the Italian version of the film, both Stanley's wife and mother-in-law are Greek.

• List of American films of 1965

• How to Murder Your Wife at IMDb  
• How to Murder Your Wife at AllMovie  
• How to Murder Your Wife at Rotten Tomatoes  
• How to Murder Your Wife at the American Film Institute Catalog  
• How to Murder Your Wife at the TCM Movie Database  
• Mel Keefer