Globally, 2.01 billion tonnes of municipal solid waste (MSW) were generated in 2016, about 37% of which was disposed of into landfills. This study evaluates the environmental and financial viability of producing ethanol from autoclaved MSW via fermentation. Experimental screening of four different microorganisms (i.e., S. cerevisiae, Z. mobilis, E. coli, and S. pombe) and process modelling indicate that MSW-derived ethanol can significantly reduce greenhouse gas emissions relative to gasoline (84% reduction following EU Renewable Energy Directive accounting methodology, and by 156–231% reduction following the US Energy Independence and Security Act methodology). Utilisation of wastes for biofuel production in the UK benefits from policy support and financial support for renewable fuels (Renewable Transport Fuel Certificates). Financial analysis highlights that microorganisms achieving higher ethanol yield and productivity (S. cerevisiae and Z. mobilis) can achieve financial viability with higher cumulative net present value than E. coli, S. pombe. However, the positive net present value can be achieved primarily due to the benefit of gate fees received by diverting wastes to autoclave and ethanol production (64% of total revenues), rather than from revenues from ethanol sales (7% of total revenues). Key process improvements must be achieved to improve the financial viability of ethanol production from MSW and deliver a clear advantage over waste incineration, specifically improving hydrolysis yield, reducing enzyme loading rate and, to a lesser extent, increasing solid loading rate. The results provide significant insights into the role of policy and technology development to achieve viable waste-to-biofuel systems