Desulfurization of high sulfur bauxite is an important issue in Bayer alumina production. In this study, by using two anionic sulphydryl collectors (HX, HD) as mixed collectors (PYDH), the selectivity of flotation separation between pyrite and diaspore was improved, thereby reducing the sulfur content of high sulfur bauxite and ultimately meeting the production requirements of Bayer alumina. The findings showed that under the optimized conditions of 500 g/Mg collector, 150 g/Mg inhibitor, 200 g/Mg activator, 100 g/Mg foaming agent, and a slurry pH of 9, the sulfur content of bauxite can be reduced from 3.35% to 0.33% through one rough selection, one fine selection, and one scavenging flotation. Moreover, the interaction mechanism between mixed collectors and pyrite was studied through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), Zeta potential analysis, and contact angle testing. SEM-EDS research confirmed that PYDH adsorbed on the surface of pyrite. The contact angle measurement analysis showed that compared to individual collectors, pretreated pyrite with mixed collectors had better hydrophobicity. Zeta potential, FTIR, and XPS results indicated that PYDH selectively adsorbed pyrite through chemical adsorption. The mixed collector PYDH is an effective collector for pyrite in high sulfur bauxite flotation desulfurization.