The present study comprehensively investigated the degradation of naproxen (NPX) using UV/O3/peroxymonosulfate (PMS), UV/O3, UV/PMS, and O3/PMS processes. The effects of various parameters such as PMS and ozone dosage, pH, and NPX concentration were investigated on process performance. Scavenging tests were conducted to identify the dominant radical species. The results under the optimal conditions show that the UV/O3/PMS process is highly efficient for NPX degradation within 30 min of reaction time. Synergy index was also calculated and it was found that ozonation of the UV/PMS process leads to higher removal efficiency and a synergy effect of about 25% was calculated. It was also found that after complete destruction of NPX molecules, 76.9% of TOC was also removed. The final degradation by-products was tracked and it was proved that hydroxylation and decarboxylation were the main pathways in NPX degradation in the UV/O3/PMS reactor. It was also proved that •OH was the main oxidizing agent in the UV/O3/PMS and accordingly the degradation mechanism of NPX was suggested. Cytotoxicity assessment of the process effluent indicated a noticeable reduction in the toxicity of the NPX-laden solution after treatment using UV/ O3/PMS process. Furthermore, cost analysis of the different oxidation processes for real wastewater indicated that UV/ O3/PMS is the most cost-effective process compared to that of other processes (112US$/m3). Accordingly, it can be put forth that the UV/O3/PMS process is a promising and reliable process for the degradation of naproxen.