To meet the demands for resources, food and energy, especially in fast developing countries in the Global South, new infrastructure investments, technologies and supply chains are required. It is essential to manage a transition that minimises the impacts on global environmental degradation while benefits local socio-economic development. Food-bioenergy integration optimising natural capital resources and considering wider environmental and socio-economic sustainability offers a way forward. This study presents an integrative approach enabling whole systems modelling to address the interlinkage and interaction of resource-food-bioenergy systems and optimise supply chains considering poly-centric decision spaces. Life cycle sustainability assessment, optimisation, agent-based modelling and simulation were coupled to build an integrated systems modelling framework applicable to the resource-food-bioenergy nexus. The model building blocks are described before their applications in three case studies addressing agricultural residues and macro-fungi in the Philippines, sugar cane biorefineries in South Africa, and Nipa palm biofuel in Thailand. Our case studies revealed the great potential of untapped biomass including agricultural waste and non-food biomass grown on marginal lands. Two value chain integration case studies – i.e. straw-fungi-energy in Philippines and sugar-energy in Africa – have been suggested as sustainable solutions to recover waste as value-added products to meet food and energy security. Case studies highlight how an integrative modelling framework can be applied to address multi-level questions, taking into account decision-making at different levels, which contribute to an overall sustainability goal.