The potential benefits of zero-valent iron-activated persulfate (Na2S2O8) oxidation in enhanced dewaterability of sludge, along with the associated mechanisms were investigated in this study. The sludge dewaterability was evaluated in terms of specific resistance to filtration (SRF) and water content. Based on these indexes, it was observed that ZVI-S2O82 oxidation effectively improved sludge dewaterability. The optimal conditions to give preferable dewaterability were found when the molar ratio of ZVI/S2O82− was 5:1 and pH value was 3.0. The most important mechanism was proposed to be the degradation of extracellular polymeric substances (EPS) incorporated in sludge flocs and rupture of microbial cells. Three-dimensional excitation–emission matrix fluorescence spectra revealed that the powerful SO4− and ·OH generated from ZVI-S2O82− system destroyed the particular functional groups of ﬂuorescing substances (aromatic protein-like and tryptophan protein-like substances), resulting in the release of bound water and the subsequent enhancement of dewaterability. Therefore, ZVI/S2O82− oxidation is an alternative approach showing great potential to be applied in sludge treatment plants.