The play is a farcical comedy revolving around the Brewster family, descended from the Mayflower settlers, but now composed of insane homicidal maniacs. The hero, Mortimer Brewster, is a drama critic who must deal with his crazy, homicidal family and local police in Brooklyn, New York, as he debates whether to go through with his recent promise to marry the woman he loves, Elaine Harper, who lives next door and is the daughter of the local minister.

His family includes two spinster aunts who have taken to murdering lonely old men by poisoning them with a glass of home-made elderberry wine laced with arsenic, strychnine, and "just a pinch" of cyanide; a brother who believes he is Theodore Roosevelt and digs locks for the Panama Canal in the cellar of the Brewster home (which then serve as graves for the aunts' victims; he thinks that they died of yellow fever); and a murderous brother who has received plastic surgery performed by an alcoholic accomplice, Dr. Einstein (a character based on real-life gangland surgeon Joseph Moran) to conceal his identity, and now looks like horror-film actor Boris Karloff (a self-referential joke, as the part was originally played on Broadway by Karloff).

The film adaptation follows the same basic plot, with a few minor changes.

August Strindberg is referenced by the character Mortimer Brewster when he compares the stories of his eccentric, and frequently murderous and disturbed, family as being as if "...Strindberg wrote Hellzapoppin."