Distilleries generate high COD (chemical oxygen demand) wastewater streams that are anaerobically digested to produce biogas with sub-optimal yields. In this work, for the first time, novel vortex-based hydrodynamic cavitation (HC) pre-treatment of these waste streams was investigated for significantly enhancing biogas yields. Molasses spent wash (120,000 ppm COD, India) and vinasse (27,000 ppm COD, Brazil) were pre-treated at varying number of passes (between 1 and 20) through the HC device at constant inflow, biochemical methanation potential (BMP) was measured and described using a first order model. Vortex-based HC pre-treatment led to 14% enhancement (2 passes) in BMP from spent wash (difficult to digest compared to vinasse) with a net energy gain of 1 GJ/ton COD. 10–22% increase in biogas yields from large-scale industrial spent wash digesters confirmed the laboratory findings. The work presented is useful and can be translated to recalcitrant feedstock for enhancing valorization using vortex-based HC pre-treatment.