The presence of antibiotics in water bodies has received increasing attention since they are continuously introduced and detected in the environment and may cause unpredictable environmental hazards and risks. The photocatalytic degradation of sulfamethoxazole (SMX) by ZnO in the presence of fluoride ions (F-ZnO) was evaluated. The effects of operating parameters on the efficiency of SMX removal were investigated by using response surface methodology (RSM). Under the optimum condition, i.e. photocatalyst dosage = 1.48 g/L, pH 4.7, airflow rate = 2.5 L/min and the concentration of fluoride ions = 2.505 mM, about 97% SMX removal was achieved by F-ZnO after 30 min of reaction. The mechanism of reactions, COD removal efficiency and reaction kinetics were also investigated under optimum operating conditions. In addition, about 85% COD reduction was obtained after 90 min photocatalytic reaction. The pseudo-first-order kinetics rate constants for the photodegradation of SMX were found to be 0.099, 0.058 and 0.048 min-1 by F-ZnO, ZnO and TiO2 (P25), respectively. The figure-of-merit electrical energy per order (EEO) was used for estimating the electrical energy efficiency, which was shown to be considerably lower than the energy consumption for the reported research on removal of SMX by photocatalytic degradation under UV irradiation. Toxicity assays were conducted by measuring the inhibition percentage (PI) towards E. coli bacteria strain and by agar well diffusion method. The results showed that after 30 min of reaction, the toxicity of the treated solutions by all photocatalysts fell within the non-toxic range; however, the reduction in toxicity by F-ZnO was faster than those by ZnO and P25. Despite the positive effects of surface fluorination of ZnO on the SMX and COD removal and reaction kinetics, its lower stability compared to ZnO and P25 in the repeated experiments gave rise to some doubts about its performance from a practical point of view.