Escherichia coli (E. coli), a typical fecal coliform, can enter surface rivers through daily wastewater and septic effluents, as well as the use of fecal fertilizers. Pathogenic strains of E. coli pose a significant public health risk. Despite China’s rapid economic and social development, sanitation and watershed management still face challenges. In this study, we employ a combined model of the Soil and Water Assessment Tool and Quantitative Microbial Risk Assessment to predict pollution changes, considering social development and climate change. Our aim is to quantify the risks and assess pollution prevention strategies for E. coli in the Three Gorges Reservoir (TGR) region. The results indicated that under moderate development, the average E. coli concentrations and disease burdens were 367 ± 75 CFU/100 mL and 23.4 (95 % Confidence Interval (CI): 2.8–72.6) Disability-Adjusted Life Years (DALYs, per 1,000,000 population per year), respectively. Under rapid development, these values were 330 ± 58 CFU/100 mL and 21.2 (95 % CI: 2.6–65.1) DALYs, respectively. Implementing a point strategy, mainly increasing sewage collection rates, could reduce E. coli concentrations by approximately 30 % and disease burdens by 27–28 %. For a diffuse strategy, primarily extending composting duration, reductions of 9 % in E. coli concentrations and 7–8 % in disease burdens were observed. Combining both strategies resulted in a 40 % decrease in E. coli concentrations and 35–36 % reduction in disease burdens. This model, incorporating social development, climate change, and microbial risk, provides insights into predicting pollution changes and evaluating the effectiveness of prevention strategies for E. coli in the TGR region and similar watersheds.