Antidepressants are released into the aquatic environment because of their incomplete removal from wastewater treatment plants. In the present work, we investigated the photochemical degradation of a commonly prescribed antidepressant, namely sertraline, in aqueous matrices. The molar absorption coefficient of sertraline at 254 nm and at various pH values in the range from 4.0 to 9.0 was 444±65 L•mol–1•cm–1, while the quantum yield of its direct photolysis under UVC radiation (λ = 254 nm) was (1.7±0.1) × 10−2 mol∙einstein−1 (i.e., both values were relatively low). Next, we investigated the photochemical degradation of sertraline under UVC radiation in the presence of hydrogen peroxide, H2O2 (i.e., UVC/H2O2) or persulfate ions, S2O82− (i.e., UVC/PS). Several parameters were studied, such as the initial concentrations of the oxidants, solution pH, and the composition of the aqueous matrix (experiments were carried out in aqueous phosphate buffers, in synthetic wastewater, as well as in synthetic fresh and hydrolyzed human urine). It was found that, in all aqueous matrices, the photochemical degradation of sertraline followed pseudo first-order kinetics. The values of the observed pseudo first-order rate constants in the UVC/H2O2 and UVC/PS processes were from one to three orders of magnitude higher than the corresponding value in the UVC process. The UVC/PS process was more efficient than the UVC/H2O2 process, either in aqueous phosphate buffer solutions or in synthetic wastewaters, despite the comparable reactivity of sertraline towards hydroxyl and sulfate radicals. However, both processes resulted in partial mineralization of the compound after prolonged irradiation. In the UVC/H2O2 process, there was an optimum H2O2 concentration which depended on the aqueous matrix, while in the UVC/PS process, there was an almost linear increase in treatment efficiency as a function of PS concentration, at least in the range of concentrations studied in the present work. Solution pH in the range from 6.0 to 9.0 had a relatively negligible effect on treatment performance for both processes. In synthetic urine matrices, despite the reduction in reaction rate (the observed pseudo first-order rate constants were reduced by approximately one to two orders of magnitude), the photochemical degradation of sertraline proceeded to a relatively satisfactory degree. Finally, the calculations of the electrical energy per order and the associated cost showed that the UVC/H2O2 and UVC/PS processes are cost-efficient and suitable for full-scale applications.