Abstract: The depression of quartz is very important for the flotation of lead−zinc oxide ore. In the system with dodecylamine as the collector, the use of sodium silicate alone has a weaker depression effect on quartz. Therefore, it is of great significance to reinforce the research on the depression of quartz. The effect and depression mechanism of Mg²⁺ and sodium silicate as combined depressant on quartz flotation behavior were studied through single mineral flotation experiments, adsorption capacity tests, Zeta potential analysis, XPS detection, and molecular dynamics simulations. The single mineral flotation test showed that the combination of Mg²⁺ and sodium silicate had a strong depression effect on quartz. The recovery of quartz was 90.15% at pH=9.7 and sodium silicate dosage of 2×10⁻⁴ mol/L. While the recovery of quartz was only 3.15% after the addition of 8×10⁻⁴ mol/L Mg²⁺. Zeta potential analysis and adsorption capacity determination indicated that, compared to adding sodium silicate alone, the amount of DDA adsorbed on the surface of quartz decreased by 95% in the presence of Mg−sodium silicate. XPS measurements and flotation solution chemistry indicated that Mg²⁺ reacts with SiO(OH)₃⁻ in the solution to form an ionic polymer. The ionic polymer can weakly physically adsorbed on quartz surface and hinder the adsorption of the collector dodecylamine, thereby achieving depression of quartz. Molecular dynamics simulation showed that Mg²⁺ enhances the depression effect of sodium silicate, which makes the decrease of DDA concentration on the quartz surface. Therefore, the combined depressant Mg−sodium silicate has a stronger depression effect on quartz.