It is critical for reliable infrastructure planning to address the Food-Energy-Water-Waste (FEW2) nexus at system level. This paper presents the applicability of resilience.io platform across water, energy and waste sectors (including food and agricultural waste) with focus on waste-to-energy pathway, aiming to establish the optimal FEW2 nexus based on economic and environmental indicators. A rich array of technology options, including water production facilities, clean energy technologies and waste-to-energy conversions are evaluated to meet the demand of water and energy (mainly gas and electricity), and the treatment requirement of waste and wastewater. A case study of Hunter Region, the largest region in Australia, is presented in this study, featuring the supply and demand context of developed countries. A full set of scenarios, including business-as-usual (BAU), water and wastewater, power plant decommission, waste-to-energy and policy intervention, is created to present FEW2 nexus from the perspective of individual nodes and the whole system. The results signal the benefits of biogas and syngas generation from anaerobic digestion and gasification for waste-to-energy pathway, alongside findings in water and energy sectors. The outcome of this analysis can then form the foundation of regional planning involving relevant stakeholders, with the modelling tools supporting scenario evaluation and collaborative learning to reach consensus in view of different performance indicators including financial and environmental metrics.