Protagonist 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 who Meg is sure 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 which is leaving him short of breath. Their mother, a microbiologist, suspects it may be located upon his mitochondria and their symbiotic farandolae.
One afternoon, Charles Wallace tells Meg of a "drive of dragons" in their back yard, 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 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, and travel inside one of his mitochondria, to persuade a larval farandola, named Sporos, to accept its role as a mature fara, against the urgings of an Echthros. 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 is saved.