With accelerated and uncontrolled developments, large amount of untreated wastes is discharged into river water courses through various open drains. Though rivers possess self-purifying capacity, water withdrawals for different beneficial uses have impacted it significantly by reducing its flow. Presently, sustainability has also become an important affair of river basin planning and management. Therefore, assessment of behavior of river under sustainability criteria is necessary. However, the uncertainty and complexity associated with the sustainability criteria, randomness of hydrologic variables, decision-makers, and missing data have become a concern for water managers. Such problems can be modeled under fuzzy logic framework. The present work develops a comprehensive artificial intelligence approach, namely ‘MATLAB Fuzzy Inference system’ to determine the self-purifying capacity of the River Ganges. Thirty-three wastewater drains are identified, which discharge untreated wastes along Kanpur–Varanasi stretch of Ganges. Critical water quality parameters have been analyzed and impact of discharge of river at 12 sampling stations is studied. The model developed to measure the sustainability is flexible to incorporate spatial/temporal changes. Final results give emphatic information to water authorities to maintain adequate flow in the river needed to dilute the waste and also in determining the treatment technology and capacity for open drains.