Removal of naproxen (NAP) present in wastewater has been studied using an improved approach based on hydrodynamic cavitation (HC), combined with ozone or hydrogen peroxide as pretreatment for biological oxidation. Initially, the operating conditions for pretreatment based on HC reactor has been optimized as an inlet pressure of 4 bar and pH 3, where the maximum extents of degradation of NAP (28.9%) and chemical oxygen demand (COD) reduction (11.3%) were achieved using the approach of HC operated individually. Combined approaches of HC with hydrogen peroxide (HC+H2O2) and ozone (HC + O-3) were also investigated for maximizing the removal of NAP from wastewater. Almost 100% NAP degradation with a COD reduction of 40% was obtained for the combined approach of HC + O-3 in 40 min, whereas HC + H2O2 resulted in 80% degradation with COD reduction of 24% within 120 min of treatment. The effluent obtained from the best pretreatment approach of HC + O-3 was further treated using aerobic oxidation based on activated sludge, and it was observed that similar to 89.5% COD reduction was achieved in the subsequent operation. Use of only aerobic oxidation resulted in 36.7% as the COD reduction and 20.4% as the biochemical oxygen demand (BOD) reduction. The biodegradability index (BI) was calculated for the raw effluent without any pretreatment, as well as for effluent subjected to HC + O-3 pretreatment. The increased value of biodegradability index, BI (from 0.35 to 0.70) and also the kinetic analysis of biological process revealed the improvement in biological oxidation using pretreatment based on HC and ozone. Also, the operational costs for different treatment approaches were calculated based on the power consumption. Overall, significant benefits using combination of ozone and hydrodynamic cavitation with aerobic oxidation have been demonstrated.