In this study the photochemical transformation of fentanyl—a very potent opioid drug—under simulated solar radiation was investigated for the first time. This pharmaceutical is frequently detected in various environment samples at concentrations that should be regarded as potentially harmful. Nevertheless, to date, no drug phototransformation products (TPs) have been reported. Considering fentanyl's exceptionally high toxicity, knowledge of the properties of these potential TPs is essential in order to properly assess its pollution impact. In this study, all photolytic experiments were performed using a xenon lamp (D65 filter) and RP-UHPLC coupled with the ESI-high-resolution tandem mass spectrometry. The phototransformation of fentanyl in natural river water and the application of heterogeneous photocatalysis as a possible way of decontaminating water were also investigated. Fentanyl turned out to be photostable, but twenty-six previously unreported TPs (formed mainly as a consequence of hydroxylation and oxidation) were found and characterized. The applied catalysts—TiO2 and ZnO—showed very high effectiveness, and the presence of the natural water matrix further increased the photodecomposition rate (up to 600 times) relative to direct photolysis. Importantly, the almost complete degradation of the parent compound as well as its TPs after 16 min of irradiation indicated that heterogeneous photocatalysis can be considered an efficient way of treatment of fentanyl-contaminated water. The computational analysis of toxicity showed that fentanyl may be more harmful to rodents and aquatic species than its TPs. However, some of these products are probably more mutagenic and developmentally toxic. Additionally, one product in particular may be a strong estrogenic compound, proving the importance of assessing TPs' toxic properties. The evaluation of bioaccumulation, bioconcentration and biodegradability revealed that fentanyl possesses unfavorable properties compared to TPs.