Climate change has economic, environmental, and social impacts that can threaten the access to water resources of several communities across the globe. Mismanagement of other sectors, like food or energy, may further reduce the water security of those communities, whilst the implementation of adequate policies and practices in those areas may operate as a path towards mitigation and adaptation. Several scholars have used the “water-energy-food nexus” as a conceptual tool for grasping both, the positive and negative interactions between those three systems. Their characterization and inclusion of polycentric knowledge at local level constitutes a fundamental step in the process of designing and implementing proposals for the sustainable management of natural resources. This study explores strategies for the sustainable management of water, energy, and food resources, emphasizing the valuation of related ecosystem services in the Andes-Pacific transboundary catchment of Ecuador and Colombia (Mira-Mataje—11,791 km2). Remotely-sensed and globally available datasets were used in the spatially distributed assessment model Co$tingNature, to identify some interactions of the water, energy, and food related ecosystems (water provision, fuelwood, and grazing respectively), aiming to characterize their fundamental synergies and trade-offs. Subsequently, the polycentric knowledge from stakeholder’s: Non-Governmental Organizations (NGOs), community leaders, academics, and a State sector worker was analysed. We found that some services related to energy (fuelwood) and food (grazing) production have negative effects on water security along the catchment. We identified a significant overlapping between ecosystem services rich areas and ancestral territories of ethnic communities, and recognized some key anthropic intensive activities that challenge the conservation of water resources. In addition, we confirm the paramount dependency of Andean cities from water provision from the mountains. We identified a widespread perception among stakeholders that WEF-related ecosystem services are at risk under global change and that, in different ways, all are taking action to adapt toward such change. We also identified the important role that culture plays in the local communities’ efforts both to defend their territory and to find sustainable practices oriented towards securing collective welfare and the conservation of the environmental integrity of their natural heritage.