Potato is a staple food crop in the agro-pastoral ecotone (APE) of North China. However, the potato yield is low and highly variable due to limited water and nutrient availabilities in the region. Irrigation and nitrogen (N) fertilization have been used widely to enhance potato yield but result in negative environmental impacts in the APE. This study aims to explore the optimum combinations of irrigation and N fertilization for different potato production goals by using APSIM-Potato model calibrated well by field experiments with different combinations of irrigation and N fertilizer conducted at the typical site in the APE. Long-term (1981–2010) simulation for potato yield, water use efficiency (WUE), nitrogen use efficiency (NUE), economic profits and environmental impacts were analyzed under different combinations of irrigation (IR, based on the soil water deficit, ranged from 10 (IR₁₀) to 100 mm (IR₁₀₀) with the interval of 10 mm) and N fertilization (ranged from 0 (N₀) to 210 (N₂₁₀) kg ha⁻¹ with the interval of 30 kg ha⁻¹). Combination of IR₁₀ and N₂₁₀ maximized potato yields in the whole APE, and the yield was highest in the middle APE, with the value of 35.2 t ha⁻¹, which was 6.7% and 2.1% higher than that in the eastern and western APE. However, such water and nitrogen managements would cause annual decline of groundwater table by 1.6 m and N loss by 10.9 kg ha⁻¹. In order to achieve the highest WUE, the irrigation amounts should be 124, 107 and 132 mm in the eastern, middle and western APE, respectively, coupled with 90 kg ha⁻¹ N fertilizer, and the highest WUEs were 89.6 kg ha⁻¹ mm⁻¹, 93.1 kg ha⁻¹ mm⁻¹ and 84.8 kg ha⁻¹ mm⁻¹ in the eastern, middle and western APE. For highest FNUE, the combination should be IR₁₀ and N₃₀ across APE, and the highest values were 959 kg ha⁻¹ kg⁻¹, 1092 kg ha⁻¹ kg⁻¹ and 1022 kg ha⁻¹ kg⁻¹ in the eastern, middle and western APE. Moreover, to get the highest income, the irrigation ranged from IR₅₀ to IR₁₀ and the amounts of N fertilizers ranged from 30 kg ha⁻¹ to 120 kg ha⁻¹, and the maximum incomes were 18,250 CNY ha⁻¹, 20,060 CNY ha⁻¹ and 19,660 CNY ha⁻¹ in the eastern, middle and western APE. In all, the combination that maximized the income could contain the relative higher yield, WUE, NUE and lower environmental sequence. Our study would be helpful in determining the optimal amounts of irrigation and N fertilization for different goals of potato production in the APE.