The present work successfully establishes the degradation of metformin, an antidiabetic drug, using vortex flow-based hydrodynamic cavitation (HC) and process intensification. Studies were carried out on a pilot plant (1 m 3 /h) and for high initial concentrations, 10−20 mg/L. Effects of intensifications using aeration and the addition of hydrogen peroxide on various process parameters were evaluated. A low degradation (3−5%) by HC at ΔP of 1 bar could be improved by process intensification using hydrogen peroxide (33%). Importantly, a very high 95% metformin degradation was obtained at pH 4 with excellent cavitational yields up to 162 × 10 −5 mg/J, further extending to 100% the degradation using HC+H 2 O 2 , an order of magnitude enhancement of 900%. The synergy can be drastically enhanced by process modifications. Per pass degradation enhancement was huge, 100 times, corresponding to an order of magnitude cost reduction compared to conventional hydrodynamic cavitation. The established strategy can have positive implications for industrial wastewater treatment.