Natural ventilation in hot climates has the potential to save energy by reducing the need to use mechanical systems. Particularly in historic buildings, it should be considered as a passive retrofit strategy before the addition of any mechanical systems to accommodate their unique indoor environmental characteristics and ensure their preservation. This study investigates the efficiency of multiple natural ventilation strategies in cooling a historic residential structure located in San Antonio, Texas, USA, a hot and humid climate area. It also analyzes their potential to provide a thermally comfortable indoor environment during the spring and summer. Onsite data and ASHRAE standards were used to create and validate Computational Fluid Dynamics (CFD) and energy models. Six different natural ventilation approaches were simulated, and the results were analyzed and compared. The analysis revealed that all the considered scenarios can contribute to energy savings in both seasons, especially in spring, with cross ventilation being the most efficient strategy. It also proved that the size of the openings has an impact on thermal comfort. This study demonstrated that historic preservation and thermal comfort goals can be achieved simultaneously, and the results can be replicated in multiple historic structures in similar climate regions around the globe.