In recent years, antibiotics have been considered as serious contaminants due to their high consumption and persistence in the aquatic environment. Currently, amoxicillin is one of the most widely used antibiotics and its emission into the environment encounters numerous health and environmental hazards. The main objectives of this research were focused on assessing the feasibility of using Fenton reagent in removing amoxicillin and determining the optimal conditions using Taguchi method. In addition, its effect on the rate of mineralization, biodegradation, and the removal efficiency of COD were studied. The Taguchi method was used to optimize variables and their levels using Qualitek-4 (w32b) software. The optimum values of the response variables were predicted using signal-to-noise ratio (S/N). The influence of different parameters including the initial concentration of amoxicillin, H2O2 concentration, Fe(II) concentration, pH, and reaction time at four different levels on the removal of amoxicillin in the aqueous phase were investigated. The removal efficiencies at initial concentrations of amoxicillin 10, 100, 200, and 500mg/L were 68.64, 95.385, 98, and 99.3%, respectively. Process optimization by Taguchi method suggests that the optimal conditions for the removal of amoxicillin in the aqueous phase are as follows: the initial amoxicillin concentration of 500mg/L, Fe(II) concentration of 5.0mg/L, H2O2 concentration of 500mg/L, pH 3, and the reaction time of 15min; and level of significance for the study parameters were 60.228, 26.369, 5.638, 4.373, and 3.392, respectively. The maximum removal efficiency of COD and mineralization rate were 71.3 and 36.3%, respectively. The biodegradation rate was also increased from 0 to 0.738. In conclusion, our study demonstrated that Fenton process may enhance the rate of amoxicillin degradation in polluted water and could be used as a pretreatment step for the biological removal. The results also indicate that the Taguchi experimental design can simply predict the optimal conditions for the removal of amoxicillin in the aqueous phase using Fenton process.