Meg Altman (Jodie Foster) is at a crossroads. Suffering through a painful divorce from her husband, pharmaceuticals millionaire Stephen Altman, Meg buys an Upper West Side Manhattan townhouse for herself and her 11-year-old daughter, Sarah (Kristen Stewart). She intends to go back to school, raise her child and start a new life. The house she chooses to purchase was built by an eccentric millionaire who built a hidden ‘panic room’ to protect himself in case of a break in.

After moving in, the need for the panic room soon comes into play when their New York brownstone home is invaded by three intruders – Burnham (Whitaker), who knows everything about the room because he built it, Raoul (Yoakam) and Junior (Leto). Meg and Sarah take a stand from the sanctuary of the panic room, not realizing that the room itself is the thieves' target... and they will stop at nothing to get inside.