The thermal comfort inside the rooms at commercial buildings is concerning the responsible people of operating these rooms as they may receive regular complaints from the occupants requesting more cooling. So, this paper presents a framework to set the ambient temperature for optimal thermal comfort in commercial buildings. Two operational parameters of the cooling systems were proposed to control the ambient temperature. The parameters are airflow and valve opening which are usually variables determined at the design stage of the cooling system. The design of experiment analysis is utilized to find the optimal setting of these parameters. Only two levels of each parameter were investigated (Low, High). A 2² complete randomized factorial design is proposed for the analysis. The framework was implemented at Alfaisal University classrooms. It was found that the optimal thermal comfort can be achieved by setting the parameters at their lower levels.