On the basis of single factor experiment, the concentration of polyethylene glycol, liquid/solid ratio, ultrasonic power and extraction time were optimized by Box-Behnken response surface analysis. Result: The results showed that the optimal extraction conditions were concentration of polyethylene glycol 68%, liquid/solid ratio 46∶1 (mL/g), ultrasonic power 157 W and extraction time 67 min. Under these conditions, the yield of polyphenols from perilla leaves reached 18.38 mg GAE/g·DW, while the predicted value was 18.21 mg GAE/g·DW, and the accuracy of the model reached 99.08%. Polyphenols from perilla leaves exhibited good antioxidant activity in a concentration-dependent manner. The IC₅₀ of polyphenols to hydroxyl radical (·OH), superoxide anion radical (O ·), 1,1-diphenyl-2-trinitrophenylhydrazine radical (DPPH·) and reducing power were 60.21, 73.44, 70.81 and 37.52 μg/mL, respectively. However, the antioxidant activity of polyphenols extracted from perilla leaves was weaker than that of ascorbic acid (V_C).