A hydrogen peroxide (H2O2) solution was adapted for microwave pretreatment of microcrystalline cellulose, which can be further used for heavy metal adsorption. The H2O2 concentration, temperature, and retention time were the key factors affecting the microwave/hydrogen peroxide pretreatment process. A Box-Benhken design (BBD) with response surface methodology (RSM) was employed to design and optimize the microwave-hydrogen peroxide pretreatment process (H2O2 pretreatment) of cellulose. After the H2O2 pretreatment, the crystallinity of cellulose decreased by 20% and the degree of polymerization (DP) decreased by up to 30%. The optimal conditions obtained by BBD were a H2O2 concentration of 8.37%, a temperature of 90 °C, and a retention time 5.33 min. Under these conditions, a minimum DP of 91.74 was achieved. The results indicated that all three of the factors notably affected the reduction of cellulose polymerization degree and pronounced interactions existed among the response variables. The predictive model developed was able to optimize the pretreatment process for the reduction of cellulose polymerization degree, which could improve the cellulose modification reactivity.