There is an increasing need to view agro-ecosystems and to identify remedial management practices in a holistic way. An integrated model based on the driving force–pressure–state–impact–response approach was developed as a tool to assess the effects of policies for improving decision making for the sustainability of agro-ecosystems. An economic model was linked to a process-based biophysical model by a meta-model. Then, a holistic indicator-based impact assessment system was linked to the integrated model to assess policy instruments. The integrated model was applied in the intensive irrigated wheat–maize cropping system of the North China Plain in which water and nitrogen fertilizer management are known to be critical issues for sustainable resource management. The results show there is a trade-off relationship between economic return and environmental outcome. It was shown that water pricing is a more effective policy instrument for improving the sustainability of agro-ecosystem than increasing the price of nitrogen fertilizer. When the water price is raised to 1.0 Yuan/m3 under a two-tariff system, the sustainability indicators for the irrigation water use efficiency was found to increase from 0.37 to 0.77, groundwater use sustainability increased from 0.05 to 0.60, nitrate leaching increased from 0.48 to 0.55 while the indicators for the farm gross margin, food self-sufficiency, and soil nitrogen balance remain unchanged. The results suggest the modeling approach developed here is very useful for evaluating policy options for complex natural resource management issues.