Climate, topography, and landscape patterns affect river water quality through processes that influence non-point source pollution. However, little is known about the response of the water quality of rivers on China’s Tibetan Plateau to these environmental factors. Based on the water quality parameters data of the Xoirong River on the Tibetan Plateau in western China, the redundancy analysis and variation partitioning analysis were adopted to determine the main influencing factors affecting river water quality and their spatial scale effects. The major water pollutants were further analyzed using the partial least square-structural equation modeling (PLS-SEM). Another mountainous river with a similar latitude, the same stream order, and low anthropogenic disturbance in central China, the Jinshui River, was also selected for comparative discussion. The results indicated that the overall river water quality on the Tibetan Plateau was superior to that of the Jinshui River. At the catchment scale, the cumulative explanatory powers of the influencing factors of both rivers were greatest. Landscape composition and configuration were the determinant factors for the overall water quality of the two rivers, while the river on the Tibetan Plateau was also significantly affected by climatic and topographical factors. Regarding the main water quality issue, i.e., total nitrogen, agricultural production activities might be the main cause of the river on the Tibetan Plateau. This study unveiled that the river water quality on the Tibetan Plateau is sensitive to climate and topography through comparative studies.