Display omitted •The first to investigate the Uronema marinum inactivation mechanism by omics.•The inactivation of Uronema marinum by UV/PDS in marine waters.•Contribution of reactive species on the inactivation of Uronema marinum.•Effect of reaction parameters on the inactivation of Uronema marinum. Protozoa in mariculture water will cause the outbreak of seafood diseases, and there are also discharge regulations about protozoa in the ballast water of ocean ships. However, the inactivation of protozoa has not attracted attention. This study investigated the inactivation of ciliate Uronema marinum (U. marinum) as surrogate for protozoa by ultraviolet (UV)/peroxydisulfate (PDS) system. Results showed that the addition of 1 mM PDS significantly enhanced the inactivation from 0.73 log to 1.47 log by UV exposure at 3.6 mJ·cm−2. Reactive species responsible for the inactivation were identified to be •SO4− and •OH. The anions in seawater inhibited the inactivation of U. marinum in UV/PDS system. UV/PDS inactivated U. marinum by damaging the cell membrane and releasing of intracellular materials. The activities change of the antioxidant enzymes showed that oxidative species destroyed the defense function. Moreover, omics analysis proved that the radicals affected the expression of genes, proteins and metabolites of U.marinum. In authentic marine water, the inactivation of U. marinum was 1.38 log in 120 s. There was no generation of chlorate (ClO3−), bromate (BrO3−) and adsorbable organic halogens (AOX). The economic cost of UV/PDS for inactivation of U. marinum was preliminarily calculated to be 0.062 $ m−3. The results suggest that it will be beneficial to upgrade UV disinfection to •SO4− based advanced oxidation technology for inactivation of protozoa in marine water.