An 11-year-old girl named Riley is uprooted from her Midwest life when her father starts a new job in San Francisco. Inside Riley's mind, her emotions—Joy, Sadness, Anger, Fear, and Disgust—lead her through everyday life. Her emotions reside in Headquarters, the control center inside Riley's mind, where they help advise her through the various trials and tribulations of growing up. Joy, Riley's main and most important emotion, tries to keep things positive, but the emotions conflict on how best to navigate a new city, house, and school.

When an unexpected event at Headquarters turns Riley's emotional world upside down, Joy and Sadness are inadvertently swept into the far reaches of her mind, which includes regions like Long-Term Memory, Imagination Land, and Dream Productions. As they journey through this mental landscape, they come across various other characters, such as Riley’s forgotten imaginary friend, Bing Bong. While Joy and Sadness struggle to find their way back to Headquarters, Anger, Fear, and Disgust are left clumsily in charge. This leads to changes in Riley's personality and her relationship with the world around her, as Joy and Sadness work together to find a way back and restore balance to Riley's emotional state.