The film opens with a young Meg Murry (Lyric Wilson) with her father Alex (Chris Pine) in their garage as he is building a device. Meg is currently awaiting the arrival of her new little brother. As her mother Kate (Gugu Mbatha-Raw) walks in, Alex talks to Meg about how powerful love is.
Years later, Meg (now played by Storm Reid) is 13-years-old, and Alex has been gone for four years, with his disappearance having remained a mystery. Meg goes downstairs to find her younger brother, Charles Wallace (Deric McCabe), in the kitchen. The two of them hear something on the radio about their father and him being missing.
At school, the other kids taunt Meg over her father's disappearance, but particularly Veronica Kiley (Rowan Blanchard). During recess, Charles Wallace overhears two teachers talking about Alex being gone, with one of them suspecting him to be having an affair. Charles Wallace calls them out on it before bringing unwanted attention to Meg. Veronica makes a snide remark about "crazy running in the family", which prompts Meg to grab a basketball and hit Veronica in the face with it. Meg is forced to see Principal Jenkins (Andre Holland), who believes Meg has been using her father's disappearance as an excuse to act out. Meg walks out of the office before Jenkins dismisses her.
Kate orders Meg to write an an apology to both Principal Jenkins and Veronica. Moments later, Charles Wallace opens the door to a stranger, a woman in a white dress with bright red hair named Mrs. Whatsit (Reese Witherspoon). She has apparently been talking to Charles Wallace for a while and knows who his mom and sister are. Mrs. Whatsit tells Kate that her husband was right and that a tesseract is real, which leaves Kate stunned.
The next day, Meg and Charles Wallace are walking their dog. They meet Calvin O'Keefe (Levi Miller), a classmate of Meg's who thought it was cool that she spiked Veronica in the face. They follow Charles Wallace as he runs into the home of a woman called Mrs. Who (Mindy Kaling), a wise woman and friend of Mrs. Whatsit who studies written works from every century.
The children return to the Murry house, where Calvin shares a meal with the family. Kate discusses what she and Alex had been trying to accomplish. We see a flashback to prior to Alex's disappearance where the two of them discussed with a group of other scientists the possibility of creating a tesseract in order to travel across the universe, but everyone laughed at what Alex was saying.
Outside, Calvin learns that Veronica is Meg's neighbor. Meg tries to get Calvin to hide because she thinks him being seen with her will damage his reputation, but Veronica has already seen them. Soon, the children are visited by Mrs. Whatsit, Mrs. Who, and the oldest and wisest of the three, Mrs. Which (Oprah Winfrey). They tell Meg that her father is still alive and that his belief in tessering is real. The Misses declare that it is time to find Alex, and they transport the children across the universe.
Everyone ends up on another planet called Uriel, which is beautiful and vibrant. The inhabitants are living flower creatures that Mrs. Whatsit communicates with. At her behest, Meg shows the flower creatures a picture of her father, whom they apparently recognize. Mrs. Whatsit transforms into a giant leaf creature and takes the kids for a ride through the sky. They find themselves flying over her back until they spot a dark cloud forming in the sky. This causes Calvin to fall, and the flower creatures catch him. Mrs. Which explains that what they saw is called "The It" (voiced by David Oyelowo), the embodiment of darkness coming from the planet Camazotz. It is responsible for the negative energy in the universe and what is keeping Alex imprisoned. We see that The It's influence spreads across Earth and is responsible for Veronica's low self-esteem, other teachers being jealous of Jenkins being promoted to principal, and Calvin's father being terrible to him for getting a less-than-perfect grade.
The Misses help the kids tesser to another planet to find the Happy Medium (Zach Galifianakis). With his help, they attempt to find a balance that will allow them to locate Alex. Meg feels she is not strong enough to do so, but the Misses help her find the strength to do so.
The Misses leave the children as they are tessered toward Camazotz to find Alex themselves. The three leave them with gifts, such as Mrs. Who's magnifying glasses, and Mrs. Whatsit giving Meg "her faults". Meg and Calvin become separated from Charles Wallace as they find themselves in a forest. Soon, a powerful storm happens that creates some kind of cyclone. Meg notices that it is launching trees to a cliff-side where they need to go. She convinces Calvin to hide inside a log and wait for the right moment. Sure enough, the log is shot across the land and makes it to the cliff where the two of them find Charles Wallace.
The kids find themselves in a neighborhood where all the children and their mothers act in synchronization. One of the mothers tries to invite the kids inside for dinner, but they decline when they feel it could be a trap. The kids keep walking until they find themselves at a beach filled with people. They are found by a man known as Red (Michael Pena). He claims to know Alex and makes it seem like he'll take the kids to find him. Red gives them food, but Charles Wallace says it tastes like sand. Red says he has passed a test, and he takes Charles Wallace with him as he reveals he is evil. Meg and Calvin chase after them until they end up in some kind of void. Charles Wallace starts acting malicious, as he is apparently possessed by the influence of The It.
Meg and Calvin are kept as prisoners, but Meg is able to move forward with the magnifying glasses to see some kind of invisible staircase and finally locate her father. The two of them reunite tearfully and embrace. They return to Calvin, but The It now has a greater hold over Charles Wallace and is threatening to keep them all as prisoners.
Meg soon finds herself within the realm of The It. It uses Charles Wallace to try and manipulate Meg into joining her. It creates a "better" copy of Meg, one with straight hair, no glasses, and an improved fashion sense. Meg rejects this and tries to save Charles Wallace. Utilizing her faults, she accepts what is not great about herself, but acknowledges that Charles Wallace loves her anyway in spite of all that. Meg's love for him proves to be more powerful than The It's hold, and it is weakened, letting Charles Wallace go.
The children reunite with the Misses, who congratulate them for succeeding in their mission. They are all tessered home. Veronica watches from her window and gives Meg a friendly wave. Calvin feels more confident in himself to go talk to his father and set things straight. The kids then enter the house with Alex, who reunites with Kate and kisses her. Meg looks up to the sky and says "Thank you".