The Zuli River is in the northwest of the Loess Plateau. As an important center of production and domestic water source, variations in the water quality of this basin and their influencing factors are important considerations for improving the river water environment. In order to identify and predict changes in the water quality of the watershed, the following water quality indicators, namely, dissolved oxygen content (DO), five-day biological oxygen demand (BOD₅), ammonia nitrogen concentration (NH₃-N), the high-manganese salt index (COD_Mn), volatile phenol concentration (VP), total phosphorus (TP), fluoride concentration (F⁻), and nitrite nitrogen concentration (NO₃-N), were studied together with their change trends, influencing factors, and main variation cycles in the basin from 2001 to 2021. The results were as follows: (1) All the water quality indicators except for DO and F- showed an increasing trend before 2011, and DO showed an extreme, significant downward trend. There was an increase in the content of pollutants in the water caused by chemical fertilizer and aquaculture, resulting in a decrease in the DO content. (2) There was an extreme, significant upward trend in DO after 2011, while a significant downward trend was observed in the other water quality indicators except for NO₃-N. (3) According to the main variation cycle of the other water quality indicators, the DO will remain in its peak period, while the other water quality indicators except for NO₃-N will remain in a trough period (which began in 2021). The increase in precipitation and runoff reduced the content of pollutants in the water. Therefore, the overall water quality of the Zuli River Basin gradually improved after 2011. This may be due to (1) increased precipitation and runoff, thereby diluting the concentration of pollutants in the river, or (2) a decreased concentration of pollutants entering the river with the decrease in soil erosion.