There is increasing interest in the harnessing of energy from waste owing to the increase in global waste generation and inadequate currently implemented waste disposal practices, such as composting, landfilling or dumping. The purpose of this study is to provide a modelling and simulation framework to analyze the technical potential of treating municipal solid waste (MSW) and refuse-derived fuel (RDF) for the polygeneration of biofuels along with district heating (DH) and power. A flexible waste gasification polygeneration facility is proposed in this study. Two types of waste—MSW and RDF—are used as feedstock for the polygeneration process. Three different gasifiers—the entrained flow gasifier (EFG), circulating fluidized bed gasifier (CFBG) and dual fluidized bed gasifier (DFBG)—are compared. The polygeneration process is designed to produce DH, power and biofuels (methane, methanol/dimethyl ether, gasoline or diesel and ammonia). Aspen Plus is used for the modelling and simulation of the polygeneration processes. Four cases with different combinations of DH, power and biofuels are assessed. The EFG shows higher energy efficiency when the polygeneration process provides DH alongside power and biofuels, whereas the DFBG and CFBG show higher efficiency when only power and biofuels are produced. RDF waste shows higher efficiency as feedstock than MSW in polygeneration process.