The study proposed the ultrasound-activated persulfate oxidation as a novel approach to enhance sludge dewaterability. The results demonstrated that the reduction of water content of dewatered sludge cake was 16.5% and the capillary suction time was reduced to 39.5 s at the optimal conditions of 1.0 mmol/g-TS S2O82- and ultrasound energy density of 2.0 kW L-1 within 15 min. The promotion of dewaterability was closely associated with the enlarged floc size, decreased viscosity, and near-neutral zeta potential. Meanwhile, the correlation analysis revealed that the protein in extracellular polymeric substances (EPS) governed sludge dewaterability, especially in loosely bound EPS. Three-dimensional excitation-emission matrix fluorescence spectroscopy, Fourier transform infrared spectroscopy and scanning electronic microscopy analysis revealed that ultrasound-activated persulfate oxidation treatment effectively degraded the gel-like EPS matrix and attacked cells, releasing the moisture which was trapped in EPS and cells. The aggregation of particles promoted the elimination of moisture. Furthermore, heavy metals in conditioned dewatered sludge cakes all satisfied the A level of agricultural land (GB4284-2018) requirements and the chemical speciation distribution of some heavy metals changed significantly.