Fe(II)-activated sodium percarbonate (SPC) was an emerging technology for enhancing the dewaterability of waste activated sludge, and its operational parameters were systematically explored. The results showed that after the treatment by 1.20 mmol/g VSS SPC and 1.44 mmol/g VSS Fe(II) at initial pH 3.0, the water content and specific resistance to filtration remained at 76.05 ± 0.36% and 2.57 ± 0.08 × 1012 m·kg−1, respectively. The acid condition was instrumental in sludge dewatering, whereas overdosing Fe(II) or SPC imposed adverse effect. The conversion of EPS fractions was examined to elucidate the underlying mechanism, which indicated that a coexisting oxidation/flocculation process accounted for the improvement of sludge dewaterability. The stronger oxidative ·OH degraded the hydrophilic compounds (proteins and carbohydrates) of tightly-bound extracellular polymeric substance and the dissolved multivalence iron promoted solid-liquid separation. Additionally, the theoretical analysis (DFT calculation) demonstrated that the oxygen- and nitrogen-containing groups of EPS resulted in high-water holding capacity of sludge. The difficulty of destroying hydrophilic functional groups followed C=O > C-N > C-O during oxidation process. Moreover, Fe(II)/SPC treatment performed well in coliforms inactivation and phytotoxicity reduction compared with different ·OH-based advanced oxidation processes for sludge conditioning.