Excess sludge reduction has been a research hotspot for a long time. Ultrasonic treatment of excess sludge was an efficient and green pretreatment method, and also can be combined with the addition of oxidants. To improve the effect of ultrasound treatment on sludge destruction, hydrogen peroxide (H2O2) was added to examine the combined results in the current study. The effects of the ultrasound/hydrogen peroxide system on the release of sludge organic matter during the destruction process were studied. Single-factor experiments were carried out to determine the optimal operating conditions. With the initial pH of 11.0, H2O2 concentration of 0.5 mmol/L, initial sludge concentration of 17 g/L, and 15 min ultrasonic treatment, the maximum soluble chemical oxygen demand (ΔSCOD) in the sludge supernatant after destruction was achieved at 3662.78 ± 239.21 mg/L, with a disintegration degree of 28.61 ± 2.14%, sludge reduction rate of 19.47 ± 0.82%, and the change of mixture sludge concentration (ΔMLSS) of 3.31 ± 0.06 g/L. Meanwhile, the release of nitrogen and phosphorus were greatly improved. Under the optimal conditions, the release of total nitrogen (TN), ammonia nitrogen (NH3-N) and total phosphorus (TP) were 282.30 ± 24.06 mg/L, 25.68 ± 2.09 mg/L, and 105.69 ± 7.84 mg/L, respectively. The current work had provided solid evidence showing the addition of hydrogen peroxide can effectively strengthen the treatment effects of ultrasound on sludge destruction.