Abstract: To clarify the impacts of national initiatives, specifically “Chemical Fertilizer and Pesticide Reduction and Efficiency Enhancement” “Livestock Manure Resource Utilization” and “Veterinary Antibiotic Use Reduction”, on multi-pollutions in the Three Gorges Reservoir Area (a critical ecological barrier in the upper Yangtze River), this study analyzed water quality data ranging from 2004 to 2021. We evaluated correlations between policy implementation and changes in nitrogen (N), phosphorus (P), antibiotics, and pesticide concentrations, addressing the research gap in regional-scale pollution control efficacy. This study combines literature review and model simulation methods to analyze the impact of changes in N, P, pesticides, and antibiotics management in crop-livestock system on multi-pollutions in the Three Gorges Reservoir Area from 2004 to 2021. Results showed: 1) After 2017, the concentrations of N, P, antibacterial antibiotic (sulfamethazine SMZ), pesticides (insecticides, fungicide) in the Three Gorges Reservoir Area decreased by 24.32%, 89.60%, 68.74%, 49.43%, and 8.20% respectively, compared with before 2017, but the concentration of antibacterial antibiotic sulfamethoxazole (SMX) increased by 12.48%; 2) In 2017, the highest N concentration areas were distributed in the middle and lower reaches of the reservoir area, such as Wujiang and Jialing rivers, while the highest pesticide and antibiotic concentration areas were distributed in rivers like the Jialing River; 3) In 2017, the N and P use efficiencies of the crop-livestock systems in the Three Gorges Reservoir Area were 21.68% and 13.16%, respectively; for the crop production subsystem, they were 25.61% and 18.88%, and for the livestock production subsystem, 13.12% and 4.62%; 4) crop and animal structure adjustments had a significant impact on N and P losses in crop-livestock subsystem. For example, in the crop production subsystem, N and P losses increased with the increase in rapeseed planting area(P<0.01); in the livestock production subsystems, the intensity of N and P losses was greatly influenced by the number of poultry and beef(P<0.01). In the future, the Three Gorges Reservoir Area should focus on changes in pesticides and antibiotic concentrations in the middle and lower reaches of the reservoir area and strengthen guidance on the scientific use of pesticides and antibiotics.