A model predictive control system is used to optimize energy cost in a variable refrigerant flow (VRF) system. The VRF system includes an outdoor subsystem and a plurality of indoor subsystems. The model predictive control system includes a high-level model predictive controller (MPC) and a plurality of low-level indoor MPCs. The high-level MPC performs a high-level optimization to generate an optimal indoor subsystem load profile for each of the plurality of indoor subsystems. The optimal indoor subsystem load profiles optimize energy cost. Each of the low-level indoor MPCs performs a low-level optimization to generate optimal indoor setpoints for one or more indoor VRF units of the corresponding indoor subsystem. The indoor setpoints can include temperature setpoints and/or refrigerant flow setpoints for the indoor VRF units.