This innovative study makes use of a thermal hydrolysis process (THP) and the conditioner sodium persulfate (SPS) to improve the dewaterability of sewage sludge. The best-operating conditions were optimized using response surface methodology (RSM): 100 mg/g of dry solids (DS) of SPS, 101 min of reaction time of THP, and a temperature of 200 °C. Distribution of extracellular polymeric substances (EPS), zeta potential, bound water, and solid characters were analyzed to reveal the mechanisms involved in the dewatering process. These results indicate that the sewage sludge after treatment (SPS combined with THP) had a superior dewaterability. The specific resistance to filtration (SRF) under the best conditions was 0.51 × 1011 m/kg, decreasing by 91.65% compared to the raw sludge (RS) (6.11 × 1011 m/kg). This mechanism could be explained as follows: (1) Aromaticity and hydrophobicity of sludge cake after SPS + THP treatment was increased; (2) sludge flocs were re-flocculated by charge neutralization, giving rise to a loose and porous structure; (3) the structure of extracellular polymeric substances and cells was destroyed, and the bound water was released. Overall, the conditioning by combination of SPS and THP is an effective mean to improve sewage sludge dewaterability. Graphical abstract.