The individual and combined depressive action of metabisulfite and dextrin on pyrite in the presence and absence of amyl xanthate has been studied through contact angle, zeta potential, microflotation, and IR spectroscopy analyses. The combined application of depressants significantly reduces the contact angle of pyrite compared with that of galena, with this effect being enhanced when the pulp is oxygenated during conditioning with metabisulfite, facilitating pyrite surface oxidation. Zeta potential measurements demonstrate the role of the oxidation process in decreasing the magnitude of the negative electric charge on the pyrite surface. These results were further corroborated by IR spectroscopy studies, which confirmed the oxidation of the pyrite surface in the presence of metabisulfite, as well as the co-adsorption of dextrin and amyl xanthate. In microflotation experiments, pyrite and galena exhibited contrasting flotation behaviors, with pyrite being effectively depressed at pH 8 when a combination of air, metabisulfite, and dextrin was used.