This study describes the optimization of polyphenol extraction from mango seed kernels by using response surface methodology (RSM). In the solid-to-liquid selection, the extraction yield, total phenolic content (TPC), antioxidant activity, and tyrosinase inhibitory activity are all significantly increased with a decrease in the solid-to-liquid ratio (P < 0.05). Between the Nam-Dok-Mai kernel (NDK) and the Tong-Dam kernel (TDK), the TDK was chosen for RSM with a fixed ratio of 1:30 solid-to-liquid. The variables in the independent processing were the concentrations of ethanol, the temperature, and the time applied to RSM. Ethanol concentration, temperature, and duration had significant individual and interactive effects on phenolic yield and antioxidant activities (P < 0.05). The optimized condition that maximized the extraction yields, TPC, and antioxidant activities from TDK was an ethanol concentration of 62 %, a temperature of 63 °C, and a duration of 150 min. The obtained and validated optimized model could be used to describe the effect of these variables on the extraction of phenolic compounds from mango seed kernels.