The pressure difference in buildings causes indoor and outdoor airflow, significantly impacting the indoor thermal environment and building energy consumption due to the introduction of outdoor air. The pressure difference in buildings is highly variable, influenced by outdoor wind speed, indoor–outdoor temperature differences, and heating, ventilating and air conditioning (HVAC) system operation, making it difficult to consider this factor during general HVAC system operation, potentially leading to an imbalance in indoor and outdoor pressure differences. Therefore, this study proposes an appropriate operation strategy for HVAC system return fans considering indoor–outdoor pressure differences. The proposed strategy involves adjusting the return fan airflow to maintain a constant indoor airflow balance, thereby controlling the indoor–outdoor pressure difference, satisfying the indoor thermal environment, and reducing HVAC system energy consumption. To evaluate the proposed strategy, dynamic simulations using TRNSYS and TRNFLOW were utilized, targeting one floor of an office building equipped with a variable air volume (VAV) system. The evaluation results showed that the maximum pressure difference decreased from −142 Pa to −18 Pa compared to the existing strategy, and the total energy consumption of the HVAC system was reduced by 29%, highlighting the importance of considering pressure differences during HVAC system operation.