Abstract: To elucidate the impacts of national initiatives, especially “chemical fertilizer and pesticide reduction and efficiency enhancement” “livestock manure resource utilization”, and “veterinary antibiotic use reduction” on multi-pollutants in the Three Gorges Reservoir Area (a critical ecological barrier in the upper Yangtze River), we analyzed water quality data in this area from 2004 to 2021, and evaluated the correlations between policy implementation and changes in nitrogen (N), phosphorus (P), antibiotic, and pesticide concentrations, addressing the research gap in the efficacy of regional-scale pollution control. In addition, we combined a literature review with model simulation methods to analyze the impact of changes in N, P, pesticide, and antibiotic management in crop-livestock system on multi-pollutants in water body in the Three Gorges Reservoir Area from 2004 to 2021. Our results showed as below. 1) After 2017, the concentrations of total N, total P, sulfadimethazine, insecticidal pesticides, and fungicidal pesticides in the Three Gorges Reservoir Area decreased by 24.32%, 89.60%, 68.74%, 49.43%, and 8.20% respectively, compared with those prior to 2018; however, the concentration of sulfamethoxazole increased by 12.48%. 2) In 2017, areas with the highest N concentration were distributed in the middle and upper reaches of the reservoir area, such as Wujiang and Jialing rivers, whereas those with highest pesticide and antibiotic concentration were distributed in rivers, such as the Jialing River. 3) In 2017, the N and P use efficiencies of the crop-livestock system in the Three Gorges Reservoir Area were 22.54% and 16.48%, respectively; those for the crop production subsystems were 19.01% and 15.27%, respectively; those for the and livestock production subsystems were 13.12% and 4.62%, respectively. 4) Crop and animal structure adjustments had a significant impact on N and P losses in crop and livestock subsystems. For example, in the crop production subsystem, N and P losses increased with increasing proportion of rapeseed sown area (P<0.01); in the livestock production subsystems, the intensity of N and P losses was greatly influenced by the proportion of numbers of poultry and beef cattle (P<0.01). In the future, research in the Three Gorges Reservoir Area should focus on changes in pesticide and antibiotic concentrations in the middle and upper reaches of the reservoir area and strengthen guidance on the scientific use of pesticides and antibiotics.