A novel technique to enhance sludge dewaterability with zero-valent iron-activated persulfate (ZVI/PDS) and hydrothermal treatment (HT) under mild temperature is proposed in this study. Key operating parameters were considered to study their influences on the dewaterability of sludge. Comparative studies of organic matter, especially extracellular polymeric substances (EPS), were analyzed carefully to reveal the mechanisms involved. The results indicated that the specific resistance to filtration declined by 86.72%, and the capillary suction time reduced by 72.35% compared with the raw sludge under optimal conditions of 100 mg/g TSS ZVI and 200 mg/g TSS PDS doses at 120 °C. Soluble protein and fulvic acid-like in EPS were the key components affecting the sludge dewatering performance. The disappearance of the peak in the amide III led to a decrease in hydrophilic functional groups, which helped to improve sludge dewaterability.