Rivers are an important mediator between human activities and the natural environment. They provide multiple functions, including irrigation, transportation, food supply, recreation, and water supply. Therefore, evaluations of water quality and pollution sources are of great significance for ecological restoration and management of rivers. In this study, the improved “vušekriterijumska optimizacija i kompromisno rješenje” (VIKOR in Serbian; in English: Multicriteria Optimization and Compromise Solution), and a geodetector were used to analyze the water quality characteristics and pollution sources of the Maotiao River Basin (Gizhou province, SW China). The results showed that the water quality of the Maotiao River Basin deteriorated significantly during the summer drought period, as was evident in the reservoirs and lakes. It improved in the wet season (i.e., during the summer period) due to runoff dilution. Water quality decreased along the river’s course, from upstream to downstream sections. The results of the geographic detector analysis showed that agricultural areas were the primary factor affecting the spatial distribution of water quality in the river basin. In July, August, and November 2020, the influence of agricultural land was 0.72, 0.60, or 0.80, respectively, and the interactions among urban, industrial, agricultural, and forested areas explained 99.2%, 83.2%, or 99.9% of the spatial differentiation of water quality, respectively. Due to the influence of spatial scale, settlements have a small influence on the spatial distribution of water quality. Their impact factors were 0.38, −0.24, and −0.05, respectively. Notably, the negative relationship of water quality and forested areas reflects that topography, types of landscapes, and soil thickness have considerable influences on the Maotiao River Basin’s water quality. Based on the findings, we infer that good farmland water conservancy projects and comprehensive management of different types of landscapes, such as forests, agriculture, and urban area and water bodies, are of great significance for improving water quality.