<p>Chloramphenicol (CAP), a broad-spectrum antibiotic extensively utilized in ocular and bacterial infection therapies, enters aquatic ecosystems predominantly through anthropogenic discharge pathways such as hospital effluents and wastewater systems, thereby posing substantial ecological and public health hazards. This investigation explores a sulfate radical-based advanced oxidation processes (SR-AOPs) leveraging FeSe₂-activated PMS for effective CAP degradation. Experimental data reveal that FeSe₂ exhibits exceptional catalytic performance in PMS activation, attaining 83.9% CAP degradation efficiency under the optimum condition. Systematic parametric analysis identified pronounced operational dependencies on pH, catalyst dosage, and PMS concentration. Radical scavenging assays confirmed SO₄^·− as the dominant reactive species, superseding HO· in degradation efficacy. The catalyst maintained superior recyclability across three successive cycles, exhibiting negligible metal leaching, a phenomenon likely attributed to synergistic Fe²⁺/Se²⁻ redox cycling mechanisms. DFT simulations coupled with LC-MS/MS analytical data pinpointed the C2 position as the principal reactive site, with degradation pathways encompassing hydroxylation, nitro-group reduction, and aromatic ring cleavage, culminating in complete CAP mineralization to CO₂. ECOSAR predictive modeling indicated a significant reduction in ecotoxicological risks among transformation products relative to the parent compound. This study not only validates the FeSe₂/PMS system as an sustainable solution for antibiotic-laden wastewater treatment but also elucidates mechanistic insights critical for metal selenide-driven SR-AOPs.</p> Graphical Abstract <p></p>