In Vietnam, banana is a popular fruit that is grown and consumed as a ripe fruit or used for cooking. During industrial processing, its peel is removed as a waste product (about 18%–33% of the whole fruit) containing many bioactive compounds useful for human health. The aim of this study was to determine the effects of extraction conditions such as the ratio of solvent to solid (ml/g), extraction temperature (oC), and extraction time (minutes) on extraction yield such as total polyphenol and flavonoid contents (TPC and TFC, respectively). The response surface methodology and Box–Behnken design were used to optimize the extraction of antioxidant compounds from “Xiem” banana peels cultivated in U Minh district, Cà Mau province, Vietnam. The results showed that the most important variable in the extraction process was solvent concentration. Optimal conditions were found to be 60%, 76:1, 68oC, and 48 minutes for solvent concentration, solvent-to-solid ratio, temperature, and time, respectively, resulting in the maximum TPC and TFC, 62.41 mgGAE/g and 6.98 mgQE/g, respectively.