Enzymatic hydrolysis of organic waste is gaining relevance as a complementary technology to conventional biological treatments. Moreover, biorefineries are emerging as a sustainable scenario to integrate waste valorization and high-value bioproducts production. However, their application on municipal solid waste is still limited. This study systematically evaluates the techno-economic feasibility of the conversion of the organic fraction of municipal solid waste (OFMSW) into high-value bioproducts through enzymatic hydrolysis. Two key variables are examined: (a) the source of the enzymes: commercial or on-site produced using OFMSW, and (b) the treatment of the solid hydrolyzate fraction: solid-state fermentation (SSF) for the production of biopesticides or anaerobic digestion for the production of energy. As a result, four different biorefinery scenarios are generated and compared in terms of profitability. Results showed that the most profitable scenario was to produce enzymes on-site and valorize the solid fraction via SSF, with an internal rate of return of 13%. This scenario led to higher profit margins (74%) and a reduced payback time (6 years), in contrast with commercial enzymes that led to an unprofitable biorefinery. Also, the simultaneous production of higher-value bioproducts and energy reduced the economic dependence of OFMSW treatment on policy instruments while remaining energetically self-sufficient. The profitability of the biorefinery scenarios evaluated was heavily dependent on the enzyme price and the efficiency of the anaerobic digestion process, highlighting the importance of cost-efficient enzyme production alternatives and high-quality OFMSW. This paper contributes to understanding the potential role of enzymes in future OFMSW biorefineries and offers economical insights on different configurations.