Tannery solid waste management posed significant environmental challenges, particularly due to the high organic load and potential toxicity of untreated fleshings. This study explored the Anaerobic co-digestion (AcoD) of chromium-free tannery fleshing, cow dung, and sewage to optimize biogas production under varying operational conditions. A multi-phase experiment was adopted, initially comparing room and controlled temperature conditions, followed by evaluations across mesophilic to lower thermophilic ranges (30–45 °C) and nine different substrate mix ratios. The highest methane yield and digestion performance were achieved at 45 °C with a substrate including a mix of fleshing, sewage, and cow dung as 1:2:1. Process parameters, primarily pH, COD reduction, volatile solid (VS) reduction, and volatile fatty acids-to-alkalinity ratio, were monitored to assess system stability. A Bayesian Network was constructed to model interdependencies among these variables, identifying temperature, initial volatile solids, and substrate-to-inoculum (S/I) ratio as key drivers of gas production. A sensitivity analysis based on mutual information and belief variance further highlighted their influence, providing a probabilistic framework for process optimization with strong interdependence, such as S/I ratio-pH (75.0%), S/I ratio-initial VS (61.5%), and VFA/Alkalinity ratio-temperature (61.6%). Thereafter, a Central Composite Design coupled with desirability analysis was used to identify optimal operational settings, followed by validation experiments, resulting only 5.6 ± 0.5% error. This study demonstrated a successful integration of experimental results and probabilistic modeling to enhance energy recovery from hazardous tannery waste, and its findings contributed to the sustainable waste-to-energy strategy as well as the circular bioeconomy.