Indoor thermal comfort represents a key aspect of building design. The reference standards do not consider the thermal adaptability of the human body, and HVAC system control strategies are based on a steady-state assumption that returns an incorrect estimate of occupants' thermal demand with a consequential misleading of the building energy consumption and of system sizing. To overcome these issues, a physiological thermal comfort model for the human body thermal behaviour evaluation is developed in MatLab environment for assessing the dynamic variation of the physiological parameters and for characterizing the occupants’ thermal sensation. Finally, the developed human body multi-node model is implemented in a building energy simulation tool (called DETECt 2.4) to perform three proposed strategies for the dynamic control of the building thermo-hygrometric parameters of the building and of the corresponding heating and cooling demands. These strategies provide an hourly regulation of relative humidity and air temperature by means of a two-step optimization that maximizes the thermal comfort of the occupants and minimizes energy consumption. To show the potentiality of the developed model, a suitable case study consisting of an office space is considered. Here, space heating and cooling demands obtained by applying the novel developed model are compared to those obtained through standard set-point values of air temperature and relative humidity (20 °C, 45% for heating needs, and 26 °C, 50% for cooling ones). By the comparison, between the proposed model – which considers the optimal hourly set point assessing the occupant in thermal evolution – and the reference ones, interesting results are obtained. Generally, a higher consumption is achieved by considering the proposed comfort strategies (from 2 to 16%), representing the price to be paid to maximize the comfort of the occupants and to annul the 3650 h of discomfort of the reference case.