Five-year old Jack lives with his 26-year old Ma in "Room," a secure single-room outbuilding containing a small kitchen, a basic bathroom, a wardrobe, a bed, and a TV set. Because it is all he has ever known, Jack believes that only Room and the things it contains (such as himself and Ma) are "real." Ma, unwilling to disappoint Jack with a life she cannot give him, allows Jack to believe that the rest of the world only exists on television. Ma tries her best to keep Jack healthy and happy via both physical and mental exercises, keeping a healthy diet, limiting TV-watching time, and adhering to strict body and oral hygiene. The only other person Jack has ever seen is "Old Nick," who visits Room at night and brings them food and necessities while Jack sleeps hidden in a wardrobe. Jack is unaware that Old Nick kidnapped Ma when she was 19 and has kept her imprisoned for the past seven years. Old Nick regularly rapes Ma; Jack is the product of one such encounter.

A week after Jack's fifth birthday, Ma learns that Old Nick has been unemployed for the past six months and is at risk of losing his home to foreclosure. Fearing that Old Nick will kill them both before freeing them, Ma comes up with a plan to convince Old Nick that Jack is deathly ill. Jack, initially unable to conceptualize being outside of Room or interacting with other people, eventually agrees. When Old Nick refuses to take Jack to a hospital, Ma wraps Jack in a rug and claims he has died. Old Nick falls for the ruse and takes Jack outside; Jack escapes and manages to reach a stranger, who contacts the police. In spite of his inability to communicate effectively, Jack describes the route to Room to an officer to free Ma.

The two are taken to a mental hospital, where they receive medical evaluations and a temporary home. Old Nick is found and faces numerous charges of abduction, rape, and child endangerment. While in the hospital, Ma is reunited with her family, learning that her parents have divorced and her brother now has a family of his own. Ma begins to relearn how to interact with the larger world, while an overwhelmed Jack yearns to return to the safety of Room. Ma's father refuses to accept Jack as his grandson. Jack also learns that before he was born, Ma gave birth to a stillborn daughter.

Meanwhile, Jack and Ma's case attracts significant mass media attention, making it harder for them to start leading a normal life. After a television interview ends badly, Ma suffers a mental breakdown and attempts suicide. While Ma is in the hospital, Jack goes to live with his grandmother and her new partner. Jack becomes increasingly frustrated with his extended family, who, while kind and loving, often fail to consider how his limited experience impacts his behavior.

After Ma recovers, she and Jack move into independent living. Jack asks to visit Room one final time. Upon returning, Jack finds that he no longer feels any emotional attachment toward it, and says his goodbyes to Room before leaving.