AbstractThe aqueous photolysis of four pharmaceuticals with varying fluorinated functional groups was assessed under neutral, alkaline, advanced oxidation, and advanced reduction conditions with varying light sources. Solar simulator quantum yields were 2.21 × 10−1 mol Ei−1 for enrofloxacin, 9.36 × 10−3 mol Ei−1 for voriconazole, and 1.49 × 10−2 mol Ei−1 for flecainide. Florfenicol direct photolysis was slow, taking 150 h for three degradation half‐lives. Bimolecular rate constants between pharmaceuticals and hydroxyl radicals were 109 to 1010 M−1 s−1. Using a combined quantitative fluorine nuclear magnetic resonance spectroscopy (19F‐NMR) and mass spectrometry approach, fluorine mass balances and photolysis product structures were elucidated. Enrofloxacin formed a variety of short‐lived fluorinated intermediates that retained the aryl F motif. Extended photolysis time led to complete aryl F mineralization to fluoride. The aliphatic F moiety on florfenicol was also mineralized to fluoride, but the resulting product was a known antibiotic (thiamphenicol). For voriconazole, the two aryl Fs contributed more to fluoride production compared with the heteroaromatic F, indicating higher stability of the heteroaromatic F motif. The two aliphatic CF3 moieties in the flecainide structure remained intact under all conditions, further supporting the stability of these moieties found in per‐ and polyfluoroalkyl substances under a variety of conditions. The advanced treatment conditions generating hydroxyl radicals or hydrated electrons accelerated the degradation, but not the defluorination, of flecainide. The combination of 19F‐NMR and mass spectrometry proved powerful in allowing identification of fluorinated products and verifying the functional groups present in the intermediates and products. The results found in the present study will aid in the understanding of which fluorinated functional groups should be incorporated into pharmaceuticals to ensure organofluorine byproducts are not formed in the environment and help determine the water‐treatment processes that effectively remove specific pharmaceuticals and more generally fluorinated motifs. Environ Toxicol Chem 2024;43:2285–2296. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.