The lysis treatment of waste active sludge (WAS) is significant to sludge dewatering/reduction and resource utilization. However, the low lysis efficiency of WAS is still a main limiting factor for the engineering application. Herein, MoS2 reinforced Fe2+/peroxydisulfate (PDS) oxidation system was unprecedentedly proposed to expedite the WAS cytolysis. The MoS2/PDS system was more effective than Fe2+/PDS system in reducing the water content of WAS, are 70.79 % and 76.38 %, respectively, at the PDS and activator dosages of 1.2 and 1.5 mmol/g volatile suspended solids. The concentrations of total organic carbon and DNA were highest in the MoS2/PDS system, were 115.12 ± 0.57 mg/L and 110.55 ± 1.65 ng/μL, respectively. The best lysis was obtained in the MoS2 + Fe2+/PDS system, which enabled a strong oxidation to excessively destroy the released organic matters. The outward discharge of organics from the intracellular and tightly bound-extracellular polymers (EPS) to loosely bound-EPS and supernatant slime-EPS was achieved with no Mo residue in the liquid phase. Of the identified active species ·OH, 1O2 and SO4•−, ·OH was found to play the most critical role in the fragmentation process for the MoS2 + Fe2+/PDS system. The MoS2-mediated Fe2+/Fe3+ cycle is favorable for the PDS activation and the formation of highly reactive radicals to accelerate the lysis reaction, thus contributing to the WAS reduction.