Intensified human-nature interactions in recent centuries have resulted in catchments functioning as a system. Managing water-related interactions in the catchment system is crucial for sustainable development. However, the information on interactions has not been coordinated at a systems-level in decision-making, which results in ineffective management across multiple spatial scales. To enable effective management, a whole-water systems modelling approach is developed and implemented to generate holistic information on these interactions for coordination. At a global scale, water-related interactions between human and natural systems result in complex dependence of social development on the environment in global countries, which leads to a worldwide imbalance in sustainable development. Two conceptual models are developed to understand the generic water-related interactions and reveal the key uncoordinated interactions that cause the imbalance, respectively. Applying the models with global datasets demonstrates that: the current decision-making of social development and water management is not sufficiently informed by their interactions with environmental state; countries’ resource dependence should be adjusted to use the global environment as a whole for achieving a balanced sustainable future for all humans. These insights are incorporated into designing management strategies that coordinate the water-related systems interactions for countries at a global scale. At a catchment scale, interactions between water system components that are not coordinated result in inefficient river water quality management. An integrated urban-rural water cycle model (CatchWat) is developed to simulate these interactions in Cherwell catchment, UK. It is found that modelling either urban or rural water cycle generates incomplete systems information for effective management. Based on the integrated simulation, a management strategy that coordinates seasonal urban-rural interventions is developed and demonstrated to increase the efficiency in river water quality improvement. CatchWat is then expanded to simulate multi-catchment interactions in the Upper Thames system, UK. The evaluated pollution contribution across sources, sub-catchments and seasons is coordinated to develop a more efficient load allocation for improving river water quality. Results show that this coordinated load allocation generates multiple benefits in improving the performance of the multi-catchment system. Finally, co-benefits and trade-offs as interactions between water management objectives are unknown in integrated urban-rural nature-based solutions (NBS) planning. A simulation optimisation framework based on CatchWat is developed to search the NBS planning that maximises water availability, water quality and flood management benefits in Norfolk, UK. Results show significant co-benefits between water quality and flood management, both of which have remarkable trade-offs with water availability. The results highlight the need to integrate water management objectives in the urban-rural NBS planning for avoiding unintended consequences. Through these case studies, the whole-water systems modelling approach is manifested as able to provide holistic information for enabling coordinated management with enhanced effectiveness at various scales. This approach can be further applied to worldwide case studies with stakeholder engagement for robust decision-making in sustainable catchment management.