Abstract: Zinc is an important raw material and nonferrous metal that has an extremely important role in the development of national economies. For this reason, countries around the world continue to strengthen their research efforts on the development and utilization of zinc resources. Sphalerite is an important source of zinc metal, which often coexists with chalcopyrite, galena, and pyrite in nature. The flotation separation of complex polymetallic sulfide ore is a difficult problem in the field of mineral processing engineering. To achieve the flotation separation of chalcopyrite, galena, and other minerals from sphalerite, depressants are needed. Due to the difficulty of activation after the depression of galena and other sulfide ores, a zinc depression and lead floatation process is usually used. The choice of the sphalerite depressant is critical when separating zinc and other sulfides. The traditional sphalerite depressants are generally inorganic. Although these depressants significantly improve the hydrophilicity of the sphalerite surface and strongly depress the sphalerite, they have a certain inhibitory effect on other sulfide ores while depressing the sphalerite. In addition, these agents are difficult to degrade and have a negative impact on the environment. To achieve high-efficiency flotation separation of sphalerite and sulfide minerals and improve the quality of the concentrate products, the development of new inhibitors is becoming increasingly important. Thence, the effect of the oxidizer potassium permanganate and organic depressant sodium alginate on the flotation of three kinds of sulfide minerals are studied, including chalcopytite, galena, and sphalerite. The investigations involved flotation tests, X-ray photoelectron spectroscopy (XPS) analysis, adsorption behavior analysis, with an additional focus on the mechanism of potassium permanganate strengthening, and sodium alginate depression of sphalerite flotation. The flotation results show that adding either an oxidizer or sodium alginate alone does not enable the selective depression of sphalerite. However, adding a certain amount of oxidizer and sodium alginate together can realize the selective coordinated depression of sphalerite, with little effect on the flotation of chalcopytite and galena. The XPS analysis results show that sodium alginate is chemically adsorbed on the sphalerite surface with oxidation products such as zinc oxide, zinc hydroxide, or zinc sulfate, but is not adsorbed on an unoxidized sphalerite surface. The adsorption test results show that the preoxidation of potassium permanganate on sphalerite significantly increases the adsorption capacity of sodium alginate on the sphalerite surface. Therefore, potassium permanganate can strengthen the sodium alginate depression of sphalerite flotation.