A Wrinkle in Time is the story of Meg Murry, a high-school-aged girl who is transported on an adventure through time and space with her younger brother Charles Wallace and her friend Calvin O'Keefe to rescue her father, a gifted scientist, from the evil forces that hold him prisoner on another planet. At the beginning of the book, Meg is a homely, awkward, but loving girl, troubled by personal insecurities and her concern for her father, who has been missing for over a year. The plot begins with the arrival of Mrs. Whatsit at the Murry house on a dark and stormy evening. Although she looks like an eccentric tramp, she is actually a celestial creature with the ability to read Meg's thoughts. She startles Meg's mother by reassuring her of the existence of a tesseract--a sort of "wrinkle" in space and time. It is through this wrinkle that Meg and her companions will travel through the fifth dimension in search of Mr. Murry.

On the afternoon following Mrs. Whatsit's visit, Meg and Charles Wallace walk over to Mrs. Whatsit's cabin. On the way, they meet Calvin O'Keefe, a popular boy in Meg's school whom Charles considers a kindred spirit. The three children learn from Mrs. Whatsit and her friends Mrs. Who and Mrs. Which that the universe is threatened by a great evil called the Dark Thing and taking the form of a giant cloud, engulfing the stars around it. Several planets have already succumbed to this evil force, including Camazotz, the planet on which Mr. Murry is imprisoned.

The three Mrs. W's transport the children to Camazotz and instruct them to remain always in each other's company while on their quest for Mr. Murry. On Camazotz, all objects and places appear exactly alike because the whole planet must conform to the terrifying rhythmic pulsation of IT, a giant disembodied brain. Charles Wallace tries to fight IT with his exceptional intelligence but is overpowered by the evil and becomes a robot-like creature mouthing the words with which IT infuses him. Under the control of IT, Charles leads Meg and Calvin to Mr. Murry and together they confront IT. However, they, too, are unable to withstand IT's power; they escape only at the last minute, when Mr. Murry appears and seizes Meg and Calvin, "tessering" away with them (traveling via another tesseract) to a gray planet called Ixchel inhabited by tall, furry beasts who care for the travelers. Charles Wallace remains possessed by IT, a prisoner of Camazotz.

On Planet Ixchel the three Mrs. W's appear once again, and Meg realizes that she must travel alone back to Camazotz to rescue her brother. Mrs. Which tells her that she has one thing that IT does not have, and this will be her weapon against the evil. However, Meg must discover this weapon for herself. When standing in the presence of IT, Meg realizes what this is: her ability to love. Thus, by concentrating on her love for Charles Wallace, she is able to restore him to his true identity. Meg releases Charles from IT's clutches and tessers with him through time and space, landing in her twin brothers' vegetable garden on Earth, where her father and Calvin stand waiting. The family joyously reunites, and the Mrs. W's visit the happy scene en route to further travels.