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Fallopia multiflora (Thunb.) Haraldson (abbreviated as F. multiflora), belonging to Polygonaceae family, has long been used in traditional medicine. Polyphenols, main compounds in F. multiflora roots, have high antioxidant, anti-inflammatory, anti-aging, etc. Processing F. multiflora roots is necessary to reduce their negative effect on liver. Study on processing red F. multiflora roots and optimizing the extraction of polyphenols from processed red F. multiflora root product is to decrease the liver toxicity and to find the optimal conditions for extract of polyphenols from processed product. This study deals with the influence of some factors including to the ratio of solvent and medicinal herbs (mL/g), extraction temperature (?C), extraction time (min) on polyphenol content and its activity in red F. multiflora roots. Raw material has been processed by the stewing method with black bean water, then by ultrasonic extraction immersed on an ES-600N device (the ultrasonic capacity of 600W, the particle size of powder of 0.5-1.0 mm). Polyphenol content and its activities were evaluated by Folin-Ciocalteu technique and DPPH method. The response surface method combined with the Box-Behnken design was used to optimize polyphenol extraction. The optimization results obtained on the raw sample were the solvent/medicinal herb ratio of 5.7/1, the extraction temperature of 42.4?C, the extraction time of 47.6 min while the optimal extraction conditions for processed sample were the solvent/medicinal herb ratio 11.2/1, extraction temperature of 53?C, extraction time of 52 min. At the optimal extraction conditions of F. multiflora roots, the polyphenol content and its activity of raw sample were 60.41?0.14 mgGAE/g and 65.98?0.22%, respectively. They were lower than those of the processed sample, 59.91?0.17 mgGAE/g and 80.18?0.21%, respectively. These results indicated that the processing is necessary for polyphenol extraction from F. multiflora roots to obtain the products having high antioxidation activity.