Abstract: The flotation separation of chalcopyrite and talc is challenging due to their similar natural floatability characteristics. Besides, it is usually difficult to effectively inhibit talc by adding sodium carboxymethyl cellulose (CMC) alone during chalcopyrite flotation. Here, a combined inhibitor comprising acidified sodium silicate (ASS) and CMC was employed to realize effective flotation separation of chalcopyrite and talc, and the combined inhibition mechanism was further investigated. Microflotation results showed that adding ASS strengthened the inhibitory effect of CMC on talc and improved the separation of chalcopyrite and talc. The zeta potential, Fourier transform infrared, and X-ray photoelectron spectroscopy analysis indicated that CMC was mainly adsorbed on the talc surface via hydroxyl and carboxyl groups. Moreover, the addition of ASS improved the adsorption of carboxyl groups. Furthermore, the adsorption experiments and apparent viscosity measurements revealed that adding ASS dispersed the pulp well, which reduced the apparent viscosity, improved the adsorption amount of CMC on the talc surface, and enhanced the inhibition of talc in chalcopyrite flotation.