The purpose of this study is to develop a comprehensive thermodynamic model of the human respiratory system and quantify the effects of inspiratory air temperature, relative humidity (RH), lung capacity and O2 fluctuation in metabolic reaction on the human respiratory system under three different physiological conditions, i.e. rest, moderate level of physical activity and extreme level of physical activity. Therefore, a second law-based analysis has carried out for the human respiratory system. It is observed that exergetic efficiency decreases by 21% and 16.5% during moderate and extreme level of activity respectively as compared to the physical condition of rest. The respiratory efficiency also increases with the increase in inspiratory air temperature and RH. For a given inspiratory air temperature, an increase in lung volume leads to a reduction in the efficiency. Increase in TV with a high airflow rate gives a higher magnitude of efficiency, such a situation appearing when a person's lung compliance harmed due to diseases. The respiratory efficiency decreases up to 2% with the increase in O2 percentage. The efficiency of the respiratory system is in maximum during rest followed by an extreme and moderate level of activity. However, with the controlled supply of O2, the efficiency of the human respiratory performance increases with the decrease in O2 percentage. Due to partial oxidation of glucose at a reduced O2 level, exergy input from the metabolic reaction is less leading to increased exergetic efficiency.