Agro-industrial waste is generated in large quantities, producing negative environmental impacts. For instance, in the distillation process of vinasses, up to 15 L are produced per alcohol produced. Therefore, it is necessary to search for ecological alternatives. Biological treatments are not recommended because vinasses contain compounds, such as melanoidins, which exert inhibitory activity against microorganisms. Thanks to this activity, melanoidins could be removed, recovered, and become a value-added product. In this study, Opuntia ficus-indica (OFI) mucilage, a natural biopolymer as coadjuvant, was used to improve the coagulation-flocculation process in the treatment of real samples of mezcal vinasses, after evaluating the individual effect of aluminum sulfate and ferric chloride. It was possible to eliminate 90% of color using ferric chloride, showing better removals than aluminum sulfate. However, the effect of ferric chloride plus OFI mucilage generated an adverse effect because the removal was under 17%. The individual effect of ferric chloride for chemical oxygen demand (COD) removal was 28%. This removal was improved by the addition of OFI mucilage, as it was able to increase removal to 84%. The natural coadjuvant was shown to be effective in the COD removal in the treatment of mezcal vinasse using the coagulation-flocculation process.