Just before a Christmas in the late 1930’s, Sheridan Whiteside, a noted radio personality, is invited to dinner at the home of Ernest W. and Daisy Stanley in Mesalia, Ohio. After slipping on ice and claiming to have dislocated his hip, he becomes an intrusive and outrageously demanding houseguest. Since he must use a wheelchair for mobility, he immediately banishes his hosts to the second floor and turns the first-floor living room and library into his personal rooms, threatening the none-too-gracious Mr. Stanley with a lawsuit to intimidate him.

An egotistical tyrant, Whiteside browbeats and manipulates everyone who comes in range. He treats his nurse, Miss Preen, with caustic insult; on others, like Dr. Bradley, he uses self-serving and dissembling flattery. Utterly selfish and shameless, he shows no concern for the feelings of others or any sense of the disruption he causes. At first, it does not seem as if his behavior can have any long-term consequences. Although he is rude to the Stanleys and their neighbors, his demands are manageable: that the Stanleys live on the second floor, keep the mornings quiet, and avoid using the telephone. The Stanleys feel they can put up with the crate of penguins, the cockroach city, and various other oddities delivered to Whiteside at their house. They can even tolerate the steady stream of his outlandish guests, which include inmates from Whiteside’s favorite charity, the Crockfield Home, a halfway house for convicts.

As Christmas approaches, however, Whiteside begins to interfere in the personal lives of the others. Whether his motives in doing so are selfish or merely thoughtless, his interference can have serious and hurtful consequences. One of the first schemes he puts in motion is an effort to seduce the Stanleys’ servants, John and Sarah, into his service. A gourmand, Whiteside appreciates Sarah’s cooking and thinks that John, her husband, might be an acceptable butler. He ignores their loyalty to the Stanleys and cajoles and flatters them without a thought of his hosts. He also begins to give pseudo-paternal advice to the Stanleys’ older children, Richard and June. He encourages young Richard to follow his dream of becoming a professional photojournalist by just hopping on a boat and steaming off to foreign ports. To June he suggests that she elope with her boyfriend, Sandy, an employee and labor organizer at her father’s factory and a young man whom Mr. Stanley intensely dislikes and had tried to fire.

Whiteside’s assistant, Maggie Cutler, falls in love with Bert Jefferson, a local newspaper reporter and aspiring playwright. Whiteside, unwilling to give Maggie up to anyone, selfishly plots to undermine her plans. At first, he tries to convince Maggie that the affair is ridiculous, but when she proves stubborn, he resorts to a deceitful scheme. Feigning interest in a new play Jefferson has written, he calls the actor and notorious vamp Lorraine Sheldon, who is en route to America on the liner Normandie and asks her to come directly to Ohio. Whiteside wants to distract Jefferson by introducing him to Miss Sheldon as a collaborator and leading lady. Maggie soon realizes Whiteside’s true intention.

After Lorraine arrives, Maggie arranges for Beverly Carlton, an actor and skilled mimic, to call Lorraine pretending to be Lord Botomley (the English peer whom Lorraine had been hoping to ensnare as a husband) and propose marriage. Unfortunately for Maggie, Whiteside discovers the deception and convinces Lorraine that she has been duped.

Whiteside’s scheme threatens to come apart from other complications, however. Dr. Bradley informs him that there is actually nothing wrong with him and that his X ray was mixed up with that of another patient. Since disclosure of that fact would have proved inconvenient, Whiteside claims to be fascinated with the doctor’s work-in-progress. Dr. Bradley is easily hoodwinked and enters a conspiracy of silence, bribed by Whiteside’s insincere promise to work with him on his manuscript. Mr. Stanley, however, is more intractable. Increasingly outraged by Whiteside’s interference in his family’s affairs, Mr. Stanley threatens to evict Whiteside, lawsuit or no lawsuit, and obtains a warrant and the service of two sheriff’s deputies. At the last minute, Whiteside saves himself by using his knowledge that Stanley’s mysterious sister is none other than Harriet Sedley, a woman who had murdered her parents with an ax.

On Christmas Day, having finally realized how serious are Maggie’s feelings for Jefferson, and prompted by his zany friend Banjo, Whiteside allows the more generous part of his character to triumph over his selfishness. He and Banjo conspire to get rid of Maggie’s competition by trapping Lorraine inside one of Whiteside’s bizarre gifts—an Egyptian mummy case. Banjo, assisted by the two deputies, then takes her to an airplane bound for Nova Scotia. That solves Maggie’s problem. The Stanleys think their problems are over, too, as Whiteside is in the process of leaving, but just as Whiteside steps on the porch, he falls on the ice again and has to be carried back inside. He immediately bellows for Miss Preen and threatens the Stanleys with a new lawsuit. Mr. Stanley throws his hands up in despair, and his wife sinks to the floor in a dead faint.