The degradation of sulfamethoxazole (SMX) by a synthesized ZnO catalyst and under UVA irradiation was examined. ZnO nanostructures were developed by a facile hydrothermal-assisted method. The effect of ZnO heating time and synthesis reaction, pH, catalyst loading, and SMX initial concentration on process efficiency was studied. Water matrices, such as humic acid (HA) solution and surface water (SW), were also used to resemble real environmental water samples. It was observed that when ZnO is synthesized at pH 7.5, nanorods grow on its surface, while nanoplatelets are formed when synthesis takes place at pH 12.5. SMX removal reached 84% after 60 min of treatment in the presence of 200 mg/L ZnO catalyst (8 h-heated at pH 7.5; C0 = 10 mg/L). The pseudo-first-order kinetic constants of SMX photodegradation were calculated at 0.039, 0.030 and 0.016 min-1 for 5, 10, and 20 mg/L SMX, respectively. This decreased efficiency was attributed to the excessive coverage of catalyst surface by SMX molecules, evidenced by SEM micrographs produced after treatment. SMX degradation in SW (12.5%) was considerably lower than in UPW (47.4%) due to the presence of natural organic matter in the first. Interestingly, SMX removal was greatly enhanced in HA matrix (99%) and this can be attributed to the ability of HA to sensitize colloidal ZnO. In all cases, morphological changes of ZnO nanostructures were observed after photocatalytic treatment. It was confirmed that SMX degradation takes place through HO• by adding HO• quenchers, such as tert-butyl alcohol and methanol, in the reactant mixture.