14-year-old Meg Murry is worried about her brother Charles Wallace, a 6-year-old genius bullied at school by the other children. The new principal of the elementary school is the former high school principal, Mr. Jenkins, who often disciplined Meg, and Meg is sure he has a grudge against her whole family. Meg tries to enlist Jenkins's help in protecting her brother but is unsuccessful. Later, Meg discovers that Charles Wallace has a progressive disease that is leaving him short of breath. Their mother, a microbiologist, suspects a dysfunction of his farandolae, invisible organelles within his mitochondria.
One afternoon, Charles Wallace tells Meg of a "drive of dragons" in their backyard, where he and Meg thereupon discover a pile of unusual feathers. Later, Meg has a frightening encounter with a monstrous facsimile of Mr. Jenkins. That night, Meg, Charles Wallace, and their friend, 16-year-old Calvin O'Keefe discover that Charles Wallace's "drive of dragons" is an extraterrestrial "cherubim" named Proginoskes (nicknamed 'Progo' by Meg), under the tutelage of the immense humanoid Blajeny, who recruits the three children to counteract the Echthroi.
Meg's first task, on the next day, is to distinguish the real Mr. Jenkins from two Echthroi doubles, by identification of the (potential) goodness in him despite her personal grudge. The protagonists then learn that Echthroi are destroying Charles Wallace's farandolae by persuading them not to root themselves in one place and mature. They travel inside one of his mitochondria to persuade a larval farandola, named Sporos, to accept its role as a mature fara. In the process, Meg is nearly annihilated, and Mr. Jenkins is invaded by his Echthros doubles; whereafter Proginoskes sacrifices himself to "fill in" the emptiness of the Echthroi, and Charles Wallace is saved.
