The ongoing industrial transformation in developing countries, including Ethiopia, has resulted in a significant increase in harmful pollutants in the environment. Various industrial activities release toxic wastewater sludge and spent yeast into the surrounding ecosystem, posing risks to public health and the environment. However, these waste materials have the potential for energy extraction and recycling. This study aimed to investigate and harness the biogas potential through anaerobic codigestion of distillery wastewater sludge and waste yeast. The researchers employed a response surface approach utilizing Box–Behnken experimental designs (BBD) to assess the three key experimental parameters influencing biogas yield: pH levels (6, 7, and 8), volume ratio (85, 92, and 99%), and temperature (33, 36.5, and 40°C). Before and after the digestion process, the researchers measured the total solids (TS), biological oxygen demand (BOD5), chemical oxygen demand (COD), and pH of all substrates. Additionally, measurements of temperature, total nitrate, and total phosphate were taken before digestion. The methane yield was modeled using a second-order polynomial through the BBD method in Design Expert software, with a p value threshold of ≤5%. The results showed that the maximum methane yield of 61.18% was achieved at a pH of 7, a temperature of 36.5°C, and a volume ratio of 92%. Conversely, the lowest methane yield of 40.13% was obtained at a pH of 6, a temperature of 33°C, and a volume ratio of 92%. The linear and quadratic values of the model (A, B, C, A2, B2, and C2) were determined to be significant terms, with p values ≤5%. Overall, the biogas yields obtained from the anaerobic codigestion of distillery wastewater and waste yeast were promising. This process has the potential to effectively remove BOD5, COD, and TS from distillery spent wash and sludge. The findings suggest that anaerobic codigestion could be a viable approach for both energy production and waste management in the setting of distillery waste.