In this work, the degradation of sulfamethoxazole (SMX) and trimethoprim (TMP) via Fenton and Fenton-like processes was evaluated using Mn2+ as supporting catalyst in the Fenton reaction. The optimum conditions of degradation were also evaluated. Besides that, the effect of independent factors pH, [H2O2], [Fe2+], [Mn2+] and reaction time (t) on the efficiency of the SMX and TMP degradation were assessed. Box–Behnken was the experimental design adopted, delineating the relative concentration (C/Co) of antibiotics after treatments as response variable. The inferences were conducted using variance analysis, Pareto chart, response surface methodology, and desirability function. Due to the lack of adjustment of the SMX degradation model, there are no more inferences about it. The significant variables (p ≤ 0.05) on TMP degradation were: reaction time quadratic and linear effect, [Fe2+] linear effect, [Mn2+] linear effect, interaction pH vs. [Mn2+]. The Mn2+ addition aided TMP degradation in environments with lower pH values. However, the addition may harm the efficiency of the antibiotic degradation at higher pH. The optimum condition for TMP degradation in the conventional process (without the addition of Mn2+) is: pH 5, [H2O2] equal to 4.41 mmol L−1, [Fe2+] equal to 0.81 mmol L−1 and 90 min reaction time.