Dried roots of Polygala tenuifolia (YuanZhi in Chinese) are widely used in Chinese herbal medicine. These components in YuanZhi have significant anti-oxidation properties owing to high levels of 3,6’-disinapoylsucrose (DISS) and Polygalaxanthone III (PolyIII). In order to efficiently extract natural medicines, response surface methodology (RSM) and least squares support vector machine (LSSVM) were used for the modeling and optimization of ultrasound-assisted extraction of DISS and PolyIII together to determine the antioxidant activity of the extracts obtained from YuanZhi. For the optimal combination of the comprehensive yield of DISS and PolyIII (Y), the Box-Behnken design (BBD) was used to improve extraction time (X₁), extraction temperature (X₂), liquid–solid ratio (X₃), and ethanol concentration (X₄). The optimal process parameters were determined to be as follows: extraction time, 93 min; liquid–solid ratio, 40 mL/g; extraction temperature, 48 °C; and ethanol concentration, 67%. With these conditions, the predictive optimal combination comprehensive evaluation value is 13.0217. It was clear that the LS-SVM model had higher accuracy in predictive and optimization capabilities, with higher antioxidant activity and lower relative deviations values, than did RSM. Hence, the LS-SVM model proved to be more effective for the analysis and improvement of the extraction process.