11-year-old Riley Anderson is uprooted from her Midwest life, when her father starts a new job in San Francisco. Riley and everyone else are guided by their emotions, Joy, Fear, Anger, Disgust and Sadness. The personified emotions live in Headquarters, the control center inside Riley's mind, where they help advise her through everyday life. As Riley and her emotions struggle to adjust to a new life in San Francisco, turmoil ensues in Headquarters when Sadness accidentally causes herself and Joy to get lost within the rest of Riley's mind, along with Riley's most important memories, known as "Core Memories". This puts Riley's mind and emotions into turmoil, as she finds herself overwhelmed and confused at her inability to feel joy or sadness.
Although Joy, Riley's main and most important emotion, tries to keep things positive, the remaining emotions conflict on how best to navigate a new city, house and school, while Joy and Sadness travel through the rest of Riley's mind, including "Long Term Memory", "Imagination Land" and "Dream Productions", in an attempt to get back to Headquarters.