Response surface methodology (RSM) coupled with a central composite design (CCD) was employed to optimize three operating conditions, namely ethanol concentration, time and temperature, for the extraction of phenolic antioxidants from artichoke leaves, demonstrated by total phenolic content (TPC), 2,2′-azinobis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) scavenging capacity and ferric reducing antioxidant power (FRAP). Analysis of variance showed that the estimating models were significant and good fit to predict the responses. Ethanol concentration and incubation temperature were the two independent variables significantly affecting the yield of phenolics and antioxidant activities. Multiresponse optimization study indicated that the optimum conditions for the extraction were extraction time of 249.3 min, incubation temperature of 70.2C and ethanol concentration of 25.17%, under which TPC of 1,011.61 mg GAE/100 g, ABTS scavenging of 65.07% and FRAP (absorbance at 700 nm) of 1.56 were predicted. No significant difference (P > 0.05) was found between predicted and experimental values, suggesting the validity of the optimization model. Practical Applications Ethanol is generally considered a safe solvent to be used in food systems. In this paper, an extraction method using ethanol as an extraction solvent has been developed, providing an economical technique to extract phenolic antioxidants from artichoke leaves.