During a cross-country lecture tour, notoriously acerbic radio personality Sheridan Whiteside slips on the icy steps of the house of the Stanleys, a prominent Ohio family, and is forced to recuperate in their home during the Christmas holidays. The overbearing, self-centered celebrity soon comes to dominate the lives of the residents and everyone else who enters the household. He encourages young adults Richard and June Stanley to pursue their dreams, much to the dismay of their conventional father Ernest. Meanwhile, Whiteside's spinster assistant Maggie Cutler finds herself attracted to local newspaperman Bert Jefferson. When she reads Bert's play, she is so impressed she asks Whiteside to show it to his contacts, and then announces she will quit his employment and marry Bert. However, her boss is loath to lose such an efficient aide and does his best to sabotage the blossoming romance...
The story is said to follow a pair of loner college undergrads, Jack and Montgomery, who order a take-out pie, but accidentally take a homemade drug that turns a two-floor journey downstairs into a “mind-bendingly transformative quest.”