Resveratrol and emodin are abundant polyhydroxy compounds that are found in the Chinese traditional medicinal herb Polygonum cuspidatum and widely used due to their excellent antioxidant properties. This study aimed to obtain the maximum extraction yields of resveratrol and emodin from P. cuspidatum via green extraction. The extracts were acquired through supercritical carbon dioxide (SC-CO2) extraction with ethanol as cosolvent. The independent variables of the extraction process, namely temperature (45-55°C), pressure (20-30 MPa), and ethanol content (80-120 mL/L), were optimized by response surface methodology. These variables had marked effects on the yields of resveratrol and emodin. Second-order polynomial mathematical models were developed and applied to predict the optimal extraction conditions (i.e., temperature of 51.8°C, pressure of 25.34 MPa, and ethanol content of 110.83 mL/L). Under these conditions, confirmatory experiments showed that the yields of resveratrol and emodin were 2.564 ± 0.121 and 2.804 ± 0.108 mg/g, respectively. High antioxidant properties, strong free radical scavenging abilities, and good reducing abilities were observed for the extracts. Resveratrol and emodin can be successfully extracted from P. cuspidatum by SC-CO2, and RSM can optimize the process. The SC-CO2 extraction of resveratrol and emodin from P. cuspidatum was developed, and RSM was successfully used to optimize the extraction parameters and predict the optimal conditions.