Low-income households in Uganda and similar tropical regions predominantly depend on natural ventilation to achieve Indoor Environmental Quality (IEQ) conditions due to limited access to and affordability of mechanical cooling systems. Factors such as building orientation, ventilation design, building envelope materials, and occupant behavior shape the effectiveness of natural ventilation in providing IEQ conditions and reducing building energy demand. Despite its significance, research on the effectiveness of natural ventilation on thermal comfort, air quality, and energy consumption in low-income tropical residences remains inadequate. This study explored the role of natural ventilation (NV), outdoor environment (OE), and building design in shaping indoor air quality (IAQ), occupant health (HI), thermal comfort, and energy consumption in low-income housing in Kampala, Uganda. A mixed-methods approach, including questionnaire surveys, the Delphi technique, statistical modeling using IBM® SPSS® Amos V24, and building simulation using IES VE V2024, were utilized to examine the relationships between variables. The findings revealed a strong positive correlation between NV, IAQ, and HI, highlighting the importance of natural ventilation in low-income households. Building factors like orientation, window type, and roofing materials impact subjective thermal comfort, with North- and East-facing homes and clay tile roofs offering better indoor conditions. Despite utilizing adaptive measures, many residents expressed dissatisfaction with the thermal environment, highlighting the need for optimized building designs, passive cooling strategies, and urban greenery to enhance comfort. Simulation results demonstrated substantial improvements in thermal comfort, Predicted Percentage of Dissatisfied (PPD), and internal gains with the test model, achieving a 44.3 % and 72.7 % annual reduction in discomfort hours above 28 °C in the living room and master bedroom, respectively. Model validation highlighted that the test model outperforms the base model and the sample buildings, highlighting the effectiveness of the proposed building envelope and orientation modifications. Utilizing the Delphi technique, the key building sustainability indicators tailored to Uganda include energy optimization, advanced construction technologies, and natural ventilation design, among others. This research provides critical insights for policymakers, practitioners, and researchers seeking to advance energy efficiency and sustainability within Uganda's built environment. These findings underscore the importance of sustainable building practices and contribute to achieving SDGs 3, 7, 11, and 13 by promoting health, energy efficiency, resilient urban environments, and reduced greenhouse gas emissions in tropical regions.