In arid regions, water is the key link sustaining both production and ecosystems, and its sustainable management is essential for regional security. This study constructs a coupled surface water–groundwater hydrology–agriculture multi-objective optimization model for the mainstream area of the Tarim River Basin, in which the NSGA-III algorithm is applied to optimize four objectives, including agricultural economic benefit per unit of irrigation water (f<sub>AB</sub>), groundwater level rise (f<sub>GL</sub>), terminal lake area (f<sub>LA</sub>), and total agricultural nitrogen load (f<sub>TN</sub>). Based on the optimized solutions, the trade-offs and synergistic pathways among multiple objectives within the water–ecosystem–agriculture system are systematically evaluated under different hydrological year conditions. The results indicate that significant trade-offs exist among objectives, with f<sub>AB</sub> showing negative relationships with f<sub>TN</sub> and f<sub>LA</sub>, and solutions with higher economic benefits generally accompanied by reduced ecological water supply and increased nitrogen loads. The spatial heterogeneity of the basin necessitates the adoption of differentiated management strategies, whereby upstream areas with relatively stable water availability can sustain higher levels of agricultural production, while midstream and downstream areas are highly sensitive to ecological water constraints and therefore require priority allocation to ecological water use. The optimization results show that cultivated land area should be dynamically adjusted under different hydrological conditions, ranging from 11.3–14.3<span> </span>×<span> </span>10⁴ hm<sup>2</sup> in wet years, 10.1–13.1<span> </span>×<span> </span>10⁴ hm<sup>2</sup> in normal years, and contracting to 9.5–11.9<span> </span>×<span> </span>10⁴ ha in dry years. The cropping structure is dominated by cotton (69.7<span> </span>%–75.8<span> </span>%), with the proportion of high-benefit crops such as vegetables and fruit crops moderately increased in wet years, whereas in dry years the structure shifts toward water-saving crops and high water-consuming crops are appropriately restricted. This study demonstrates that combining multi-objective optimization with spatially differentiated regulation can achieve coordinated management of water resources, ecosystems, and agriculture, and provides an operational decision-making basis for managing water–ecosystem–agriculture systems in arid inland river basins.