Talc exhibits excellent floatability and, as a major silicate gangue mineral associated with chalcopyrite, significantly obstructs the purification and smelting of chalcopyrite. This study investigates the reverse flotation separation of chalcopyrite and talc using KMnO4 as a depressant and DDA (dodecylamine) as a collector within a reverse flotation system. Single mineral flotation experiments show that after adding KMnO4, the recovery of chalcopyrite in 38–74 μm is only 6.86 %, whereas the recovery of talc in 45–106 μm and 25–45 μm are 93.47 % and 89.25 %, respectively. Further experiments with artificially mixed ores demonstrate that KMnO4 effectively achieves the separation of chalcopyrite and talc. The depression mechanism of KMnO4 on chalcopyrite and talc was analyzed using Zeta potential, contact angle measurement, AFM (atomic force microscopy), FTIR (Fourier transform infrared spectroscopy), XPS (X-ray photoelectron spectroscopy), and DFT (density functional theory) calculations. Mechanistic analysis indicates that in an alkaline environment, chalcopyrite can undergo a redox reaction with KMnO4, forming hydrophilic hydroxide species (Cu(OH)2, Fe(OH)3) on the chalcopyrite surface, which depresses chalcopyrite flotation. In contrast, the surface properties of talc are relatively stable and difficult to react with KMnO4, which cannot depress the flotation of talc. Therefore, KMnO4 can be used as an efficient and selective depressant for the reverse flotation separation of chalcopyrite and talc.