A partitioned governance mode, in the absence of multilateral cooperation, always culminates in recurring instances of trans-boundary conflicts and critical degradation of water bodies in border regions. Addressing the existing gaps in quantitative trans-boundary pollution control research in extensive river network, a new approach was designed to strategically guide water pollution control initiatives throughout the entire tri-border region of the Yangtze Delta (TBYD) via the following steps: (1) Building upon an analysis of the trans-boundary river hydrodynamics, the tri-border effective coordination scope (TECS), i.e., a strategic coordination scope for coordinated pollution control, was delineated, and 13 county-level administrative districts were identified as effective contributing regions for detailed coordination. (2) Considering water quality standard (WQS) attainment in the trans-boundary cross-sections, a one-dimensional mathematical model covering the complex river network was established. Then, the load capacities for all the contributing administrative regions were determined to facilitate coordinated pollution load reduction across the TECS. (3) Leveraging from the sewage treatment costs within the TECS, a standardized eco-compensation criterion was established to guide the coordinated compensation practices across the TECS. (4) By comparing the practical pollution discharging amount, the coordinated load reduction rates and eco-compensation payments of all 13 contributing administrative districts for trans-boundary pollution control were assessed. These assessments will guide policy promulgation and provide quantitative data support for harmonizing pollution control policymaking and addressing intricate trans-boundary pollution issues in complex river networks.