Acid whey is a by-product of the dairy industry that should be utilized or appropriately neutralized. Anaerobic processes represent a group of prospective methods for whey processing, and a key priority in their development is to improve their technological and economical effectiveness. The present study aimed to determine the effect of ultrasonic disintegration (UD) of acid whey on the course and effectiveness of methane fermentation. The study results demonstrated that extending the UD duration resulted in increased concentrations of dissolved forms of COD and TOC, efficiency of organic matter biodegradation, and CH4 production. The best effects were achieved at 900 s US, including CH4 production of 0.203 ± 0.01 dm3/gCODin. and CH4 content accounting for 70.9 ± 2.8%. Organic compounds were removed with the following efficiencies: COD—78.7 ± 2.1%, TOC—80.2 ± 1.3%, and BOD5—84.1 ± 1.6%. The highest net energy gain of 5.763 Wh was achieved upon UD of 300 s. Extension of UD time had no significant effect on the improvement in the energetic effectiveness of anaerobic digestion. A strong positive correlation was found between COD and TOC concentrations in the dissolved phase and CH4 production yield.