As China’s urbanization progresses, thermal environmental problems such as the overheating effect experienced by cities are becoming more and more obvious in the daily lives of residents. Urban waterfront spaces not only create pleasant landscape environments and regulate microclimates, but also help to maintain ecological diversity. However, the current high-density urban construction model has led to poor air mobility and weakened water regulation functions in cities. Therefore, the rationalization of the spatial form of settlements has become particularly important in recent times. In this study, the Nan Lake area of Wuhan City was taken as the research object, and it was simulated using ENVI-met (5.5.1) software. Further, the orthogonal experimental design method was combined with the extremum difference analysis method. This study focused on the effects of the layout form (LF), floor area ratio (FAR), green form (GF), and offshore distance (OD) on the temperature (T), relative humidity (RH), and thermal comfort in waterfront settlements in summer. This study found that (1) among the various factors, the effect of the GFs and LFs on the overall microclimate of the study region was the most significant, while the volume ratio had the least significant effect on each indicator. (2) The parallel layout form was found to have better ventilation effects compared to the other three layout forms, with its cooling and humidifying effects being superior. (3) Among the four types of greening combinations, the combination of “grass + shrubs” had the best cooling effect at the height of pedestrians, while trees were able to reduce the heat transfer of solar radiation to the ground due to the shading and evaporation effects provided by their canopies. (4) The cooling and humidifying effects provided by the water body of Nan Lake gradually diminished as the distance from its shore increased; therefore, waterfront settlements maintaining a reasonable proximity to their water bodies will help bring into play the microclimate adjustment effect of such bodies. This study provides a valuable reference for the construction and renewal of urban waterfront settlements in the hot summer and cold winter zones of China (HSCW).