This work is focused on the kinetics, mineralization, and toxicological assessments of the antidepressant drug amitriptyline hydrochloride (AMI) in UV or solar illuminated aqueous suspensions of ZnO, TiO2 Degussa P25, and TiO2 Hombikat. ZnO was proven to be the most effective photocatalyst, and it was used for all further experiments under solar irradiation. The highest reaction rate was observed at 1.0 mg/mL of catalyst loading. In the investigated initial concentration range (0.0075–0.3000 mmol/L), the degradation rate of AMI increased with the increase of initial concentration in the investigated range. The effects of H2O2, (NH4)2S2O8, and KBrO3, acting as electron acceptors, along with molecular oxygen were also studied. By studying the effects of ethanol and NaI as a hydroxyl radical and hole scavenger, respectively, it was shown that the heterogeneous catalysis takes place mainly via free hydroxyl radicals. In the mineralization study, AMI photocatalytic degradation resulted in ~30% of total organic carbon (TOC) decrease after 240 min of irradiation; acetate and formate were produced as the organic intermediates; NH4+, NO3−, NO2− ions were detected as nitrogen byproducts. Toxicity assessment using different mammalian cell lines, showed that H-4-II-E was the most sensitive one.