Nowadays, large open spaces are popular in office buildings. However, occupants often complain about too cold and/or too warm in large open spaces. It remains a challenge to control the operation of air-conditioning systems to provide occupant comfort due to the ununiform distribution of airflow, internal heat gains and occupancy. Previous studies using CFD tools or building energy modelling tools alone did not solve the combined problem of the distributive temperature field in the space and the cooling demand from multiple terminal units. This study proposed to divide the large space into multiple subzone areas based on the layout of the terminal cooling equipment and the distribution of internal heat gains and occupancy. Regarding the uneven thermal environment among subzones, a coupling of FLUENT with EnergyPlus is used to compute the optimal thermostat setpoint for each subzone to ensure uniform occupant comfort in the large space. EnergyPlus computes the interior wall surface temperatures and terminal unit supply air flowrate of each subzone, which are passed to the CFD simulations as boundary conditions; while FLUENT simulates the temperature and PMV field with user defined function (UDF), as well as airflow rates across the virtual partition walls between two adjacent subzones, which are passed to EnergyPlus for consideration as inter-zone airflow. A case study using open office space in Hong Kong is conducted to demonstrate the validity of the methodology. Different temperature setpoints were estimated for the subzones, and the results indicated the subzone-based temperature setpoint could achieve uniform occupant thermal comfort and avoid overcooling. In addition, the coupling method improves the prediction accuracy of cooling energy than the standalone EnergyPlus program. Therefore, the coupling method can effectively provide a thermally comfortable environment with less energy use in large open office served by multiple terminal units.