Whiskey distillery waste streams consisting of pot ale (liquid residue) and spent grain (solid residue) are high strength organic wastes and suitable feedstock for anaerobic digestion (AD) from both economic and environmental stand points. Anaerobic digestion of pot ale and pot ale/spent grain mixtures (with mixing ratios of 1:1, 1:3, and 1:5 by wet weight) was performed after implementation of a novel hybrid pre-treatment (combined chemical and mechanical) in order to modify lignocellulosic structure and ultimately enhance digestion yield. Lignin, hemicellulose, and cellulose fractions were determined before and after chemical pre-treatment. Effects of different inoculum rates (10–30–50% on wet basis) and beating times (0–7.5–15 min) on anaerobic digestion of pot ale alone and of pot ale/spent grain mixtures were investigated in lab scale batch mode with a major focus of optimising biogas yield by using response surface methodology (RSM) in Design Expert Software. The highest biogas yields of 629 ± 8.5 mL/g vs. (51.3% CH4) and 360 ± 10 mL/g vs. (55.0 ± 0.4) with anaerobic digestion of pot ale alone and spent grain mix after 1M NaOH and 7.5 min beating pre-treatments with 50% inoculum ratio respectively. The optimum digestion conditions to maximise the biogas quality and quantity were predicted as 10 and 13 min beating times and 32 and 38 ◦C digestion temperatures for anaerobic digestion of pot ale alone and spent grain mix respectively.