Response surface methodology accompanied by Central Composite Design (CCD) was employed in this study to optimize Alternanthera spp-based phytoremediation process for the removal of acetaminophen and methylparaben individually. Two operational variables, including concentration (A) (20, 60,100 mg/L) and sampling time (B) (7, 14, 21, and 35 days) were involved in the study for removal efficiency (Y) as response. CCD had required a total of 18 experiments for each compound. Analysis of variance (ANOVA) was conducted to verify the adequacy of the proposed mathematical models and revealed good agreement with the experimental data. The observed R2 values (0.9732 and 0.9870), adjusted R2 (0.9620 and 0.9816) and predicted R2 (0.9383 and 0.9721) for AC and MP, respectively, indicated that the developed models were significant at the 95% probability level. Concentration factor was found to be not significant in the mathematical models; in contrast, sampling time was found to be of a crucial role. The removal of AC and MP were 89.23% and 64.48% at optimum conditions of A = 100 mg/L and B = 35 days respectively. Validation test confirmed the predicted results attained by Central Composite Design, as the removals achieved at the optimum conditions was 91.04% and 59.17% for AC and MP, respectively, which were in good agreement with the results proposed by the theoretical design.