High-solid anaerobic digestion (HS-AD) is one of the most efficient and popular solid-waste-treatment and energy-recovery technologies. However, it is significantly influenced by composition and substrate characteristics, with the carbon-to-nitrogen ratio (C/N ratio) and biodegradability being important. In this study, the substrate was adjusted and compounded to investigate the methanogenesis performance with the substrate C/N ratio (2.82–82.72) and biodegradability (refractory and easily degraded) variation during HS-AD. The results showed that the highest methane yield (MY) was achieved with white meat (273.02 mL/g-VS), which was 2.22 times higher than that of substrates with higher C/N ratios. However, this enhanced methane productivity was accompanied by elevated total ammonia nitrogen (TAN) concentrations, which substantially increased the risk of system instability. For a high C/N ratio (>50:1), the difference between the C/N ratio and biodegradability had little influence on MY, and under a low C/N ratio (<5:1), the methane production rate was higher. For low C/N substrates, acetic (14.53–76.82%) accounted for the highest total volatile fatty acids (VFAs) during HS-AD, and for high C/N ratio substrates, propionic (46.44–82.66%) had a higher proportion (r = 0.94). An increased C/N ratio decreased total ammonia nitrogen (TAN) and alkalinity (p < 0.05). Variations in the C/N ratio and biodegradability led to differences in the microbial composition.