Urbanization has intensified the urban heat island effect, reducing outdoor thermal comfort and discouraging physical activity, which negatively impacts public health. Waterfront green spaces, integrating water bodies and vegetation, are vital for microclimate regulation and enhancing urban residents' thermal comfort and well-being. However, the mechanisms by which different blue-green space configurations influence thermal comfort remain unclear. This study focuses on optimizing the layout of waterfront green spaces to improve thermal comfort, using the Qinhuai River in Nanjing as a case study. ENVI-met simulations were employed to analyze the effects of water body morphology, green space orientation and layout on the Physiological Equivalent Temperature (PET). Results indicate that complex water body forms, such as Bagua-shaped layouts, achieve the best performance. Green spaces parallel to prevailing winds enhance thermal comfort within 10 meters, while perpendicular orientations maximize cooling in downwind areas. Centrally arranged green spaces reduce summer PET by up to 12.3°C and improve winter PET by 3.2°C compared to dispersed layouts. Based on these findings, optimization strategies for green space planning have been proposed and applied to the Qinhuai River, demonstrating significant improvements in thermal comfort. This study provides actionable insights for urban planners, supporting the “Healthy China 2030” initiative by promoting healthier and more climate-resilient urban environments.