This study was aimed to optimize the extraction process of hyperoside from leaves ofAcanthopanax senticosusby compounding-enzyme method and orthogonal experiment. The hyperoside compound was regarded as standard and determined by HPLC. Based on the experiments of 4 factors including the enzyme amount, temperature, extraction time and PH values, the extraction process of hyperoside was determined by the orthogonal experiments and variance analysis. The results of single-factor experiments showed that different enzymes showed different effects on the enhance yield of hyperoside. The effects of different factors showed that the order of PH, neutral protease, temperature, time, pectinase, xylanase and cellulose was from strong to weak. Through orthogonal analysis, the optimum conditions were 2% pectinase, 2% xylanase, 0.5% neutral protease, and 0.5% cellulose, under the temperature of 30°C, extraction time of 10 min, and pH = 4.5. Under these conditions, the extraction rate was 1.84%. The yield was increased 107% compared with traditional process. It was concluded that the use of compounding enzyme can increase the yield of hyperoside, which possessed a lot of economic benefits.