Linking water to research on coupled human and natural systems (CHANS) has attracted wide interest as a means of supporting human-natural sustainability. However, most current research does not focus on water environmental properties; instead, it is at the stage of holistic status assessment and measures adjustment from the point of view of the whole study region without revealing the dynamic interaction between human activities and natural processes. This paper establishes an integrated model that combines a System Dynamics model, a Cell Automaton model and a Multiagent Systems model and exploits the potential of the combined model to reveal regions' human-water interaction status during the process of urban evolution, identify the main pollution sources and spatial units, and provide the explicit space-time measurements needed to enhance local human-natural sustainability. The successful application of the integrated model in the case study of Changzhou City, China reveals the following. (1) As the city's development has progressed, the water environment status in some spatial units is still unsatisfactory and may even become more serious, especially in the urban areas of the Urban District and Liyang County. The concentration of Chemical Oxygen Demand (COD) in monitoring section 157 of the Urban District has increased from 36.90 mg/l to 40.84 mg/l. The main source of this increase is the increase in secondary industry. (2) With the application of the spatially explicit measures of the sewage treatment ratio improvement and new sewage plant construction, the water quality in the urban area has significantly improved and now satisfies the water quality standards. The measure of livestock manure utilization enhancement is adopted to improve the spatial units in which livestock is the main pollution source and achieve the goal of water quality improvement. The model can be used to support the sustainable status assessment of human-water interaction and to identify effective measures that can be used to realize human-water sustainability along with social-economic development.