This study investigates the Humic Acid (HA) degradation in aqueous solution by a Fenton-Like process using Fe2+ and Mn4+ as a catalyst. The effect of the independent factors: pH, [H2O2], [Fe2+], [Mn4+] and t (reaction time) at the efficiency of HA degradation were evaluated, aiming at obtaining the optimum conditions. The statistic arrangement adopted was the Central Composite Design, and the response variable was the HA relative concentration after the treatments. The inferences were made using variance analysis, the Pareto chart, the response surface method and the desirability function. The variables which were more significant at the HA degradation were: [Fe2+] (linear and square effects), pH (square effect) and the interactions between [Fe2+] vs [H2O2] and [Fe2+] vs t. The addition of Mn4+ did not provide a significant improvement to the efficiency of HA degradation. Nevertheless, it was observed that the conventional Fenton process proved to be an efficient alternative for the HA degradation. The optimal and most economical condition is pH 5, [H2O2] of 6.17 mmol L−1, [Fe2+] of 0.54 mmol L−1, reaction time of 120 min and no added Mn4+.