China is rich in sea buckthorn (Hippophae rhamnoides L.) resources and a large amount of sea buckthorn fruit is used to extract oil and juice every year. However, Sea Buckthorn Leaves (SBL), which are full of flavonoids, are discarded as waste. To make full use of resources and turn waste into valuables, the optimal purification process of flavonoids from SBL was studied and the antioxidant activities of Crude SBL Flavonoids (CFSBL) and Purified Flavonoids (PFSBL) were compared. The macroporous resin which was most suitable for the purification of CFSBL was selected by comparing the flavonoid content, adsorption rate, desorption rate, and recovery rate in eluant. The purification process of CFSBL was optimized by a single factor, Analytic Hierarchy Process (AHP) and Response Surface Methodology (RSM). 1,1-Diphenyl-2-Picrylhydrazyl (DPPH), hydroxyl radical, and reducing power methods were used to determine the antioxidant activity of CFSBL and PFSBL, respectively. AB-8 macroporous resin was optimized for purification and the optimal process was determined by RSM combined with AHP: The ethanol concentration was 82.93%, and the sample concentration and elution velocity were 0.09 and 1.71 mL/min, respectively. The purity of PFSBL was 84.2%, which was 6.53 times higher than that before purification and the recovery rate was 69.5%. The scavenging IC50 of DPPH, hydroxyl radical, and reducing the power of CFSBL were 0.016, 1.501, and 0.146 mg/mL, respectively. PFSBL were 0.002, 1.131 and 0.051 mg/mL, respectively. The antioxidant activity of PFSBL was improved compared with that of CFSBL. SBL can be considered a potential source of antioxidants in food and industry. The purification process in this study can enhance the antioxidant activity of SBL. © 2022 Jiale Shan, Yang Liu, Pu Zhao, Hongli Zhou and Peng Wan.