Anaerobic co-digestion (AcoD) is becoming increasingly popular in the biogas industry for its numerous advantages over mono-digestion, including balanced nutrient profiles, enhanced process stability, synergistic methane production, and reduced greenhouse gas emissions. However, varying results across AcoD studies highlight the need for an extensive meta-analysis of a large data set to better understand these synergies. Here, we compared methane yields from 432 data sets, based on the ratio of means, from AcoD and mono-digestion. The relative synergistic index (RSI) revealed synergistic effects in AcoD of lignocellulosic biomass with animal manures, particularly pig (RSI = 1.91) and chicken manures (RSI = 1.71). Due to its rapid biodegradability, food waste AcoD also demonstrated synergistic effects with both animal manures (RSI = 1.28) and lignocellulosic biomass (RSI = 1.41). After regrouping data by high-carbon cosubstrates, interpretable machine learning models identified temperature, which accelerates the hydrolysis of lignocellulosic biomass and emulsification of fats, oils, and grease, as the key factor influencing methane yield. Furthermore, experimental validation using food waste and sewage sludge co-digestion confirmed the superiority of multivariable linear regression in predicting specific methane yield over other models in terms of simplicity and efficiency.