Aiming at the problem that lead-zinc mineral processing wastewater has an adverse effect on zinc oxide flotation, the main reasons why the wastewater affects the zinc oxide flotation are studied, and the mechanism of the influence of the mineral processing wastewater on the zinc oxide flotation is revealed. The effects of pH value and concentration of various metal ions on zinc oxide flotation in lead-zinc mineral processing wastewater were investigated. The results show that calcium ions have a greater impact on zinc oxide, mainly because they affect the adsorption of collectors on the mineral surface. Sodium carbonate can eliminate the influence of calcium ions in wastewater and improve zinc oxide flotation. The research provides a reference for wastewater reuse and improving the utilization rate of zinc oxide resources.