<p>Water quality serves as a key indicator for assessing the effectiveness and success of water diversion efforts, yet comprehensive assessments of water pollution risk across interbasin areas remain scarce. Therefore, considering water quality standards, water eutrophication, and drinking water safety, a comprehensive water quality risk inedx (CRI) was developed by integrating the Comprehensive Pollution Index (CPI), Eutrophication Index (TLI), and New Water Quality Index (NWQI). This framework was designed to determine the spatiotemporal risk levels at a spatial scale that crosses large river basins. The Jiangsu section, pivotal water supply source for the eastern route of the South-to-North Water Diversion Project (SNWDP-ER), was selected as the study area. In addition, based on the long-term (2003–2022) water quality monitoring data, multiple statistical methods were used to evaluate the effects of the SNWDP-ER on water quality within the lakes and main reaches of the Jiangsu Section. Variance analysis revealed significant differences in water quality pre- and post-water transfer and the operation of SNWDP-ER has contributed to the improvement of overall water quality. Principal Component Analysis (PCA) identified the predominant parameters affecting water quality was converted from COD_Mn to NH₃-N and TP after water transfer and the main objective of water quality control in the study area is agricultural non-point source pollution. The comprehensive water quality risk assessment identified three groups with distinct risk levels and the impact of water transfer project on the water quality risk of reaches was gradually increasing from upstream to downstream. This study greatly enhanced our understanding of the impacts of large-scale water transfer projects on water quality and proposed a comprehensive framework for assessing spatiotemporal risk levels across extensive river basins.</p>