Ultrasonic irradiation as a pretreatment of Fenton-acclimation treatment was investigated to enhance the efficiency of sludge reduction and effectiveness of operating cost. A series of batch experiments were conducted to optimize the reaction conditions for ultrasonic–Fenton treatment. Separate ultrasonic treatment suggested that input power of 0.4 W/mL and ultrasonic time of 10 min were the optimal conditions for sludge disintegration, and the efficiency was reduced with the increase of sludge mixed liquor suspended solids. Separate Fenton treatment revealed that 9 g/L and 40 mg/L were the optimal dosages of H2O2 and Fe2+ respectively for sludge lysis under pH of 3. Particle distribution (75.49% of the particles distributed between 7.18 and 31.11 μm after Fenton treatment while 93.35% of the particles distributed between 4.62 and 18.50 μm after ultrasonic–Fenton treatment) and chemical oxygen demand (51.89% higher in ultrasonic–Fenton treatment than that in Fenton treatment) demonstrated that combined ultrasonic–Fenton treatment was effective in sludge disintegration compared to separate Fenton treatment. With ultrasound as pretreatment, sludge reduction rate increased from 26.53 to 63.59% with operating cost reduction of 51.46%, indicating ultrasonic irradiation was effective in improving both sludge reduction efficiency and operating cost-effectiveness.