To enhance the effect of sludge disintegration, we proposed the following two-stage process and a new index: (1) dispersion of sludge to facilitate homogeneity and to reduce the size of flocs; (2) destruction of zoogloea and bacterial cells; energy disintegration ratio (EDR=DDCOD/E-S) was used to evaluate this process energy efficiency. Thus, a combined homogenate+ultrasonic (H+U) method was implemented to disintegrate sludge. The analysis of the disintegration degree (DDCOD), EDR, and particle size distribution revealed the high efficiency of the H+U pretreatment method for sludge disintegration. And it also turned out that EDR was an important rational index for sludge disintegration. Transmission electron microscope images showed intuitive evidence for sludge disintegration of the two-stage process. According to the central composite design and response surface methodology results, the second-order response surface model can adequately predict sludge disintegration. The optimal condition was sludge disintegration of 12min (H of 2min and U of 10min). DDCOD, EDR, and median particle size were 28.9, 7.01%, and 7.8m, respectively. These results also proved the effectiveness of the proposed two-stage process. Moreover, the selection of effective disintegration methods that correspond to sludge characteristics could increase the efficiency of sludge disintegration and reduce the amount of energy consumed in the process.