The efficiency of sludge dewatering is affected by the structure and composition of hydrated extracellular polymeric substances (EPS). Degrading EPS can improve the sludge dewatering performance. As an oxidizing agent, sodium periodate (NaIO 4 ) has ability to oxidize organics, which is expected to decompose the protein and polysaccharide in EPS and improve the efficiency of sludge dewaterability. This study adopted NaIO 4 , for the first time, as an advanced oxidation agent to regulate EPS of waste activated sludge and was combined with anionic polyacrylamide (APAM) as a flocculant to subsequently enhance sludge dewatering. Response surface methodology (RSM) was used to determine the optimal conditions of pH, NaIO 4 , and APAM. The results showed that the composite conditioner's specific resistance of filtration (SRF) and the water content of the vacuum-filtered cake (Wc) were highly enhanced compared with those of the raw sludge (RS) under pH 6.5, a NaIO 4 concentration of 50 mg/g dry solids (DS), and an APAM concentration of 5 mg/g DS. Owing to the pre-oxidation achieved by NaIO 4 under a mildly acid environment, sludge flocs were broken. Subsequently, chemical coagulation (APAM) agglomerated the smaller particles into larger flocs of sludge by adsorption and bridging, thus improving sludge dewaterability. © 2021 Water Environment Federation • Practitioner points • A novel conditioner, pH/NaIO 4 /APAM, was explored for sludge dewatering. • IO 3 • and HO• oxidized extracellular polymeric substances (EPS). • Degradation of the protein content of EPS released bound water. • Highly enhanced sludge dewaterability was achieved under optimal conditions.