ABSTRACT Talc is a naturally hydrophobic mineral. Its separation from sulfide minerals is a tough issue in froth flotation. In this study, calcium lignosulphonate (CLS) was introduced as a talc depressant during sodium isobutyl xanthate (SIBX) flotation of chalcopyrite. The micro-flotation findings showed that under pH 5.0–10.5, the combination application of CLS and SIBX achieved a selective flotation separation of chalcopyrite from talc. The results of zeta potential, contact angle, adsorption capacity and in-situ AFM deduced that both talc and chalcopyrite exhibited a favorable affinity toward CLS, and SIBX hardly changed the adsorption of CLS on talc surface, while significantly reduced that on chalcopyrite. The Ca2+ ions of CLS played a bridging role in connecting lignosulphonate (LS) anions and the negatively charged Si-O layers through electrostatic attraction, which transformed talc surface from hydrophobicity into hydrophilicity. The Cl− ions weakened the adsorption of LS anions on the Ca2+-modified talc surface, and the adsorption affinity of Na+ ion toward the Si-O layers was much weaker than that of Ca2+ ion. Thus, CLS exhibited the strongest depression against talc’s floatability, followed by CaCl2 + SLS (sodium lignosulphonate), and then SLS. SIBX chemisorbed on to chalcopyrite via forming the surface Cu-IBX complexes, which removed the adsorbed LS anions and recovered the floatability of chalcopyrite. The CLS-hydrophilized talc and SIBX-hydrophobized chalcopyrite exhibited the different surface wettability, and they both loaded negative charges, which prevented the aggregation of their particles, resulting in a highly efficient flotation separation chalcopyrite from talc.