The book opens on Thanksgiving evening, 10 years after the events of A Wind in the Door . Meg is now married to Calvin and is expecting their first child. Calvin has become a scientist and is in Britain at a conference; and Meg's family is joined for Thanksgiving dinner by Calvin's mother, Branwen Maddox O'Keefe. When they receive the news of impending nuclear war caused by the dictator "Mad Dog Branzillo", Mrs. O'Keefe lays a charge on Charles Wallace to prevent the disaster by means of "Patrick's Rune": a rhyming prayer of protection inherited from her Irish grandmother.
Charles Wallace goes to the star-watching rock, a family haunt, where his recitation summons a winged unicorn named Gaudior, who explains to Charles Wallace that he must prevent nuclear war by traveling through time and telepathically merging with people who lived in the locale of the star-watching rock at points in the past. They are threatened along the way by the Echthroi, the antagonists introduced in A Wind in the Door , who now seek to alter history in their favor. Gaudior and Charles Wallace's travels bring them to Harcels, a Native American boy at least 1,000 years in the past; Madoc of Wales, a pre-Columbian trans-oceanic traveler; Brandon Llawcae, a Welsh settler in puritan times; Mrs. O'Keefe's brother Chuck Maddox, during their childhood; and Matthew Maddox, a writer during the American Civil War. Throughout their journey, Meg connects with Charles Wallace from home through "kything", the telepathic communication she learned in A Wind in the Door . Gradually, it is revealed that Branzillo is a descendant of Madoc through all Charles' other alter-egos, and of Madoc's treacherous brother Gwydyr; and ultimately, Charles' manipulation of Branzillo's various ancestors, results in the re-union of Madoc's line, and the transformation of the present Branzillo into an advocate of peace, to prevent the war.
Throughout the story, this poem is invoked by Charles Wallace through the personalities he inhabits, to ensure the victory of good. The poem features in several parts of the book, each with slightly different wording or different punctuation; the poem's definite composition is unsure. It is an abbreviated variant of Saint Patrick's Breastplate.
At Tara in this fateful hour,
I place all Heaven with its power,
And the sun with its brightness,
And the snow with its whiteness,
And the fire with all the strength it hath,
And the lightning with its rapid wrath,
And the wind with its swiftness along its path,
And the sea with its deepness,
And the rocks with their steepness,
And the Earth with its starkness
All these I place
By God's almighty help and grace
Between myself and the powers of darkness