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In order to optimize the extraction conditions of total flavonoids from Suaeda salsa, on the basis of single factor investigations, the effects of three independent variables (ethanol concentration, extraction temperature, and liquid to solid ratio) on the extraction rate of total flavonoids from S. salsa were evaluated. The optimal extraction conditions for total flavonoids extraction were determined by box-behnken design and response surface methodology (RSM). The optimal conditions to achieve the maximum yield of flavonoids from S. salsa were determined as follows: ethanol concentration 70%, extraction temperature 88.1°C, liquid to solid ratio (mL/g) 38, and extraction time 2 h. Under these optimal conditions, the extraction rate of total flavonoids from S. salsa was 5.84%. The experimental values agreed with the predicted values by experimental rechecking.