Display omitted •SMX was degraded by UV/PS system in sea water.•The active sites of SMX were calculated by density functional theory.•Neither trichloromethane nor halate was formed during the reaction.•UV/PS is relatively safer than the traditional UV/NaClO disinfection. Sulfate radical (SO4−) based advanced oxidation processes are effective for the removal of antibiotics including sulfonamides from freshwater. However, few studies were focused on the degradation of sulfonamides in marine aquaculture water and seawater, as well as the impact of transformation products on seafood such as fishes. In this work, sulfamethoxazole (SMX) was treated with UV/persulfate (UV/PS) system in different water samples. Chloride ions (Cl−) had an inhibitory effect possibly due to the consumption and mutual quenching of reactive radicals. A slight promotion by bromide ions (Br−) was observed and should be related not only to the transformation of Br, but also to the properties of the SMX itself. Bicarbonate ions (HCO3–) significantly inhibited degradation as it is a scavenger of SO4− and HO in UV/PS. Sulfate ions (SO42−) showed a negligible impact on SMX degradation. The active sites of SMX were calculated to be the N1 and C7 atoms of the isoxazole ring, as well as the C9, C13 and N3 atoms of the benzene ring. Seven organic transformation products were identified by LC-MS/MS. Bromate (BrO3−) and chloromethane as the potential human carcinogens were not detected from the reaction system of UV/PS with SMX in marine aquaculture water and seawater. Preliminary analysis of toxicity by the EPI Suite model, absorbable organic halogen (AOX) analysis and growth inhibition of Chlorella vulgaris proved that the UV/PS process could be used as a new disinfection method and it is relatively safer than traditional UV/NaClO disinfection.