Thermal comfort is crucial to well-being and work productivity. Human thermal comfort is mainly controlled by HVAC (heating, ventilation, air conditioning) systems in buildings. However, the control metrics and measurements of thermal comfort in HVAC systems are often oversimplified using limited parameters and fail to accurately control thermal comfort in indoor climates. Traditional comfort models also lack the ability to adapt to individual demands and sensations. This research developed a data-driven thermal comfort model to improve the overall thermal comfort of occupants in office buildings. An architecture based on cyber-physical system (CPS) is used to achieve these goals. A building simulation model is built to simulate multiple occupants’ behaviors in an open-space office building. Results suggest that a hybrid model can accurately predict occupants’ thermal comfort level with reasonable computing time. In addition, this model can improve occupants’ thermal comfort by 43.41% to 69.93%, while energy consumption remains the same or is slightly reduced (1.01% to 3.63%). This strategy can potentially be implemented in real-world building automation systems with appropriate sensor placement in modern buildings.