This novel is the third in a series of five books that tell the multi-generational story of the Murry family. In this book, Charles Wallace Murry is sent into the past in a desperate attempt to avert a potential present-day nuclear war. As the narrative describes his experiences slipping in and out of several time frames, it explores themes relating to the interconnectedness of past and present; the tension between will and trust; and the nature of connection with God.

The narrative begins as the Murry family prepares its traditional Thanksgiving dinner. One non-traditional element is the presence of oldest daughter Meg's mother-in-law, the elderly and unhappy Mrs. O'Keefe. The festivities are interrupted by a call to Mr. Murry from the President of the United States who often calls the brilliant Mr. Murry for advice on scientific matters. After he hangs up, Mr. Murry reveals that the President told him that South American dictator Mad Dog Branzillo has threatened to launch nuclear weapons at the United States, an act that could only result in destructive nuclear war. As the family debates the potential consequences of such a war, Mrs. O'Keefe mumbles about a rune, calls Charles Wallace "Chuck," and gives him a mission to stop Branzillo. Charles Wallace agrees. He enlists the support of Meg (with whom he has always had a special closeness), and goes out to what the family calls the star watching rock. Meg, for her part, goes upstairs to bed and falls into a kind of trance, the better to stay connected with Charles.

At the star watching rock, Charles cries out the first words of Mrs. O'Keefe's rune. He is answered by the arrival of a cranky unicorn named Gaudior, who tells him that he has been sent by the Wind, that Charles Wallace is a singer of the Old Music, and that the two of them together are to travel into the past to find a Might Have Been that could change the present if triggered. He also warns Charles Wallace that forces of darkness and destruction called Echthroi will try to block their mission. Charles Wallace climbs on Gaudior's back, and together they fly to the first of several different locations in the When, while always staying in the same Where.

An early stop for Charles Wallace and Gaudior is the far distant past. Charles Wallace's consciousness is sent into a young native boy whose connection to nature and the Old Music is strong. This, Gaudior says, is to give Charles Wallace experience at going Within. Gaudior then takes Charles Wallace (who maintains his psychic connection with the entranced Meg) on a series of journeys into the lives of Mad Dog Branzillo's ancestors, searching for the Might Have Been that will change the present. Charles Wallace, meanwhile, struggles to find the connections between his experiences and those described in a book by writer Matthew Maddox, which he senses somehow has the key to resolving his mission. Throughout their journeys, the travellers are attacked by the Echthroi, who are determined to block their mission in the same way as they (the Echthroi) have been determined, over the centuries, to bring death and destruction into the many generations of Branzillo's ancestors, and into the whole world.

Eventually, Gaudior and Charles Wallace make their way to the time and life of Matthew Maddox himself. Meg, meanwhile, is using their experiences to trace the history of Mrs. O'Keefe, discovering that she is in fact a descendent of Maddox. Eventually, having gone Within Matthew and shaped his life and choices, Charles Wallace discovers the correct Might Have Been, changes the past and in turn, transforms the present into one of peace. His return to his body is difficult and only the intervention of Meg and Mrs. O'Keefe is able to save him. After Mrs. O'Keefe leaves the Murry home, Charles Wallace tells Meg that it was Mrs. O'Keefe and not him that placed herself between the powers of darkness and the possible destruction of the earth.