A microwave-assisted extraction (MAE) technology developed to extract polyphenols from the strawberry leaves was optimized by response surface methodology (RSM). Box-Behnken design (BBD) with four-factor and three-level was used to estimate the effects of extraction time, microwave power, ethanol concentration, and liquid-solid ratio in strawberry leaf extracts on total phenolic content (TPC) and antioxidant capacity (DPPH and FRAP). The optimized conditions were extraction time of 40 s, ethanol concentration of 51.1%, microwave power of 300 W, and liquid-solid ratio of 61.6 mL/g. The TPC, inhibition percentage of DPPH radical, and FRAP were 89.21 mg GAE/g, 79.80%, and 34.62 mM FE/g under optimal conditions. The absolute errors between the experimental and predicted values were less than 5.00%, revealing that the model was fitted well. High Performance Liquid Chromatography (HPLC) analysis demonstrated that the major antioxidant polyphenols with the highest concentration extracted at the optimum conditions were sinapic acid and rutin. This study proves that the MAE technique can efficiently extract polyphenols with high antioxidant activity from strawberry leaves.