This study aimed to optimize the solid-state hydrogenogenic stage supplemented with biomass fly ash in a two-stage anaerobic digestion (AD) process for biohythane production from the organic fraction of municipal solid waste (OFMSW). Doehlert’s experimental design was used to obtain the optimal set of two investigated variables, namely total solids (TS) content and biomass fly ash dosage in the defined ranges of 0–20 g/L and 20–40%, respectively. Applying the optimal conditions of TS content (29.1%) and fly ash dosage (19.2 g/L) in the first stage led not only to a total H2 yield of 95 mL/gVSadded, which was very close to the maximum H2 yield predicted by the developed model (97 mL/gVSadded), but also to a high CH4 yield of 400 mL/gVSadded (76% of the theoretical CH4 yield). Moreover, the biohythane obtained from the optimized two-stage process met the standards of a biohythane fuel with an H2 content of 19% v/v.