Degradation of Naproxen, a common nonsteroidal anti-inflammatory drug as a model compound, has been reported using hydrodynamic cavitation (HC) and process intensification. Two types of cavitating devices, vortex diode that employs vortex flow and a conventional linear flow based device, orifice have been investigated for their effectiveness in degradation. Process intensification was carried out by employing simple aeration and also by addition of oxidising agent, hydrogen peroxide (H2O2). Vortex diode required significantly lower pressure drop (1.5 bar) compared to the orifice (5 bar). A high extent of degradation, 67%, was possible using the process intensification; representing a very high enhancement, to an extent of more than 200%, by combining HC+H2O2. The degradation of naproxen progresses via intermediates formation and intermediates also eventually get gradually degraded. The kinetics of degradation was evaluated using per pass degradation model and for the different approaches, confirming higher per-pass degradation in the vortex diode and for the process intensification. The cavitational yield in HC+H2O2+aeration using vortex diode (23.4 × 10−5 mg/J) was ∼ 5 times greater than that for orifice (4.5 × 10−5 mg/J). The present study clearly highlights utility of process intensification approach for the degradation of active pharmaceutical ingredients (API) pollutants for increased efficacy.