Clinacanthus nutans Lindau is a well-known plant, native to tropical Asian countries. Reports on this plant that is rich in phenolic compounds have focused on its therapeutic anti-inflammatory, anti-herpes simplex, antioxidant, and anti-cancer characteristics. In this paper, the influence of the extraction parameters—temperatures (60–80 °C), times (80–120 min), and solvent ratios (70:30–90:10) of water:ethanol were investigated using response surface methodology in order to determine the optimum extraction conditions that could produce maximum extraction yields of the phenolic compounds and the highest anti-radical activity of the C. nutans extract. The optimum conditions suggested by the predicted model were: an extraction temperature of 60 °C, an extraction time of 120 min and a water:ethanol solvent ratio of 90:10 v/v%. The residual standard error of 0.2% indicated that there was no significant difference between the actual and predicted values and it proved that the models were adequate to predict the relevant responses. All the independent variables had a significant effect (p < 0.05) on all the responses which indicated that all extraction parameters employed in this study were important in the optimization process. The R2 values for three responses, extraction yields, DPPH radical scavenging activity and TPC were 0.9999, 0.9999 and 0.9983 respectively, suggesting that the quadratic polynomial models developed were satisfactorily accurate to be used in analyzing the interactions of the parameters (response and independent variables). This study could be useful in the development of cosmeceutical products containing extracts of C. nutans.