IntroductionDuring the past decades, the polysaccharides from medicinal plants have attracted great attentions, due to their diverse and potentially significant pharmacological activities. The leaves of mulberry, as a folk medicine, has been traditionally used in Asian countries for purposes to treat fever, protect the liver, improve eyesight, strengthen joints, facilitate the discharge of urine, reduce blood glucose and lower blood pressure [1]. Mulberry leaves extracts have shown multi-direction biological activities, such as the antioxidant, antimicrobial, anti-inflammatory, anti-allergic, anti-atherosclerotic, and significant hypoglycemic effect [2][3][4][5][6][7]. A large amount of polysaccharides was contained in mulberry leaves, and their useful pharmacological effects, such as hypoglycemic and lipid-lowering activities, have been verified [8]. Polysaccharides from the leaves of mulberry (PLM) have displayed a broad application prospect in medicine and functional food.Extraction of polysaccharides is an important processing for its application or further research and development, which has prompted many research papers on the extraction technology of polysaccharides from plentiful of plants or fungus in recent years. Response surface methodology (RSM) was successfully used for optimizing the hot water extraction of polysaccharides from the roots of Codonopsis pilosula [9] and Prediction of optimum reaction conditions for the thermotolerant acetylxylan esterase from Neocallimastix patriciarum [10]. The advantage of RSM was that it could reduce the number of experimental trials and evaluate the interactions between multiple parameters. It is more effective and precise than many approaches. Ultrasonic technology and microwave technology were respectively applied to extract polysaccharides from Poria cocos [11] and cultured Cordyceps militaris [12], and the optimal extracted conditions were both obtained by RSM.However, there were few reports about optimization of ultrasonicmicrowave-assisted extraction (UMAE) of polysaccharides, especially Abstract Background: In this study, ultrasonic-microwave-assisted extraction (UMAE) was first applied to extract polysaccharides from the leaves of mulberry (PLM). The optimal conditions for polysaccharides extraction were determined by response surface methodology (RSM) along with central composite design (CCD) based on the singlefactor experiments. Extraction temperature (°C), extraction time (s), pH value, and ratio of water to raw material were investigated. Also, the antioxidant activities of PLM with UMAE were evaluated.