Background: The Cisadane River in South Tangerang City serves as a critical drinking water resource, yet experiences severe environmental pressures from urban runoff, structural landfill leachate risks, and untreated graywater discharge from riverside communities. This study integrated biophysical and social analyses to formulate a long-term, sustainable pollution control strategy for the river basin ecosystem. Methods: Applying a mixed-method sequential explanatory framework, water quality sampling was conducted across upstream, midstream, and downstream stations, followed by Streeter-Phelps modelling, household surveys (n = 67), interviews with Pentahelix stakeholders, multiple linear regression, and Internal Factor Analysis Summary (IFAS) and External Factor Analysis Summary (EFAS) analyses. Findings: The river basin was classified as lightly polluted, with a Pollution Index ranging from 0.58 to 4.87, mainly due to high Total Coliform loads and elevated Chemical Oxygen Demand (COD) levels (28.4 mg/L). Streeter-Phelps modelling indicated that the river retained a positive Biochemical Oxygen Demand (BOD) assimilation capacity, reflecting natural self-purification. Regression analysis identified domestic wastewater management and public cognitive perception as significant determinants of water quality, whereas littering behavior was not significant. IFAS and EFAS analyses positioned the environmental system in Quadrant I, supporting an aggressive S-O strategy. Conclusion: Sustainable pollution control should prioritize integrated environmental governance through real-time monitoring, standardized biofilter septic systems, and community-based river management. Novelty/Originality of this article: This study integrates Streeter-Phelps modelling with biophysical, socio-institutional, and Pentahelix analyses to provide a comprehensive framework for sustainable river pollution control.