Water quality management remains a challenge due to the complex interactions between multiple influencing factors. Although the influences of land use/cover types on water quality have received extensive attention, few researchers have attempted to elucidate the correlation between water body characteristics and water quality, and the interactions between water bodies and other land use/cover types on water quality have been relatively less studied. In this study, the southern Jiangsu Plain, eastern China, was taken as a study area, and the influence of water body area on water quality was investigated. The results revealed that all land use/cover types exhibited correlations with water quality, but their correlative directions and significance levels exhibited larger differences. The influences of different water body types on water quality were discrepant, and these influences all had spatial non-stationarity. The interactions between urban and dry lands and water bodies on water quality were bidirectionally weakened, and there was an inverted U-shaped relationship between water body area and water quality. The water body area could predict whether the water quality reached the standard of Class Ⅲ, and the appropriate cut-off values of the water body, rivers, and lakes were 10.65%, 9.33%, and 2.38%, respectively. These results suggested that water body area had a positive influence on water quality, and the loss of water bodies caused by the expansion of urban and dry lands created a double whammy on water quality; finally, water body area could effectively predict whether water quality reached a certain standard. Thus, maintaining a reasonable water body area contributes to managing water quality, and the proportion of water bodies can be a useful index for water quality management in downstream regions with dense river networks.