This work reports a combined coagulation-electrocoagulation process using a biocoagulant from the Opuntia ficus-indica for treatment of cheese whey wastewater. The process parameters as pH, biocoagulant dosage, and current density were evaluated from the chemometric tools. A Box-Behnken design was used, having as responses the removal percentages of turbidity and chemical oxygen demand (COD). The results showed that for the studied variable ranges, linear models were obtained and the pH was parameter more significant for treatment proposed. The pH showed synergic effect with the investigated parameters, while the biocoagulant dosage and density current showed antagonistic effects. The desirability function was used to optimization of process, and suggested values were pH 10.0, biocoagulant dosage of 4.4 g L−1, and current density of 31.5 mA cm−2, which showed removals of turbidity and COD of 98.9 and 83.8%, respectively.