Mahonia bealei (Fort.) Carr., is an economic plant cultivated in Southwest China commonly used in traditional Chinese medicine. In this study, a response surface methodology was used to optimize experimental conditions for the extraction of phenolic compounds from the leaves of Mahonia bealei (Fort.) Carr. The highest extraction ratio of phenolic compounds yielded 39.1 mg gallic acid equivalent/g of dry weight using an ethanol concentration of 30% (v/v) as a solvent and a liquid-to-solid ratio of 21:1 (mL·g-1) for 2 h in 63°C. The crude material was extracted under optimal conditions, enriched, and then purified through a D-101 macroporous adsorption resin, giving a phenolic compound-enriched fraction we named TPMB. Evaluation of its in vitro antioxidant activity suggested that TPMB significantly scavenged the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical, superoxide radical, and hydrogen peroxide in a concentration-dependent manner. In addition, TPMB also exhibited a strong reducing ability and provided protection against oxidative damage induced by oxidative stress in cellular antioxidant activity assays. The results from this study indicate the suitability of the response surface methodology in optimizing the solvent extraction of phenolic compounds from M. bealei. Further research showed that TPMB possesses a strong anti-radical activity and may be an effective oxidation resistance treatment in the medical and food industries.