Addressing the challenges of low resource-use efficiency and supply-demand mismatch in Hami melon production, this study investigated the interactive effects of irrigation and fertilization to identify an optimal regime that balances yield, water conservation, and resource-use efficiency (i.e., water use efficiency and fertilizer partial factor productivity). A greenhouse experiment was conducted in Hami, Xinjiang, employing a two-factor design with five irrigation levels (W1-W5: 60-100% of full irrigation) and three fertilization levels (F1-F3: 80-100% of standard rate), replicated three times. Growth parameters, yield, water use efficiency (WUE), and partial factor productivity of fertilizer (PFP) were evaluated and comprehensively analyzed using the entropy-weighted TOPSIS method, regression analysis, and the NSGA-II multi-objective genetic algorithm. Results demonstrated that irrigation volume was the dominant factor influencing growth and yield. The W4F3 treatment (90% irrigation with 100% fertilization) achieved the optimal outcome, yielding 75.74 t ha(-1)-a 9.71% increase over the control-while simultaneously enhancing WUE and PFP. Both the entropy-weighted TOPSIS evaluation (C = 0.998) and regression analysis (optimal irrigation level at w = 0.79, similar to 90% of full irrigation) identified W4F3 as superior. NSGA-II optimization further validated this, generating Pareto-optimal solutions highly consistent with the experimental optimum. The model-predicted optimal regime for greenhouse Hami melon in Xinjiang is an irrigation amount of 3276 m(3) ha(-1) and a fertilizer application rate of 814.8 kg ha(-1). This regime facilitates a 10% reduction in irrigation water and a 5% reduction in fertilizer input without compromising yield, alongside significantly improved resource-use efficiencies.