The biorefining of biowastes, specifically the organic fraction of municipal solid waste (OFMSW), into biofuels and high-value products is an energy-demanding process, still immature, and largely dependent on the process configuration and efficiency of employed microorganisms. Such issues might undermine the environmental sustainability of the biorefinery by inducing adverse impacts on human health, ecosystem quality, climate change, and resources, which need to be explored before the process scale-up. Hence, this study was performed as early sustainability guidance to investigate the environmental impacts of different biorefinery platforms for biofuels production from OFMSW. More specifically, three pretreatment methods (i.e., acetone organosolv, acid, and hot water), two hydrolysis treatments (i.e., acidic and enzymatic), and two fermentation alternatives (i.e., ethanolic fermentation and acetone-butanol-ethanol (ABE) fermentation) were investigated. Based on European Commission's Joint Research Center instruction, the environmental impacts were studied using consequential life cycle assessment for the macro-level decision context. The results demonstrated that ABE fermentation scenarios were not environmentally favorable because the avoided impacts from final products were not significant enough to compensate for the induced environmental burdens from acetone pretreatment. On the contrary, the ethanolic fermentation scenarios with either acid or hot water pretreatment outperformed both ABE fermentation and ethanolic fermentation with acetone pretreatment. Based on the results, the scenario including simultaneous dilute acid pretreatment and hydrolysis of OFMSW followed by ethanolic fermentation manifested the best performance in all damage categories, as compared to those including acetone pretreatment or higher consumption of enzymes. Such improvements in this scenario led to the highest net saving of −842 potentially disappeared fraction (PDF)/m2/yr, −249.95 kg CO2 eq, and −3275.22 MJ primary per ton of OFMSW on ecosystem quality, climate change, and resources, respectively, and the lowest net burden of 1.54 × 10-5 disability-adjusted life years (DALY) per ton of OFMSW on human health. The results of sensitivity analysis on this scenario demonstrated that the substitution of excess heat for marginal heat with fossil origin can considerably decrease impacts on human health.