The aim of this work is to optimize biogas production from thermophilic dry anaerobic digestion (AD) of the organic fraction of municipal solid waste (OFMSW) by comparing various operational strategies to reduce ammonia inhibition. A pilot-scale plug flow reactor (PFR) operated semi-continuously for 170 days. Three scenarios with different feedstock, namely solely OFMSW, OFMSW supplemented with structural material, and OFMSW altered to have an optimal carbon-to-nitrogen (C/N) ratio, were tested. Specific biogas production (SGP), specific methane production (SMP), the biogas production rate (GPR), and bioenergy recovery were evaluated to assess the process performance. In addition, process stability was monitored to highlight process problems, and digestate was characterized for utilization as fertilizer. The OFMSW and the structural material revealed an unbalanced content of C and N. The ammonia concentration decreased when the optimal C/N ratio was tested and was reduced by 72% if compared with feeding solely OFMSW. In such conditions, optimal biogas production was obtained, operating with an organic loading rate (OLR) equal to 12.7 gVS/(L d). In particular, the SGP result was 361.27 ± 30.52 NLbiogas/kgVS, the GPR was 5.11 NLbiogas/(Lr d), and the potential energy recovery was 8.21 ± 0.9 MJ/kgVS. Nevertheless, the digestate showed an accumulation of heavy metals and low aerobic stability.