Flotation separation of copper-sulfur at low alkalinity has attracted soaring interest in the beneficiation of copper sulfide ore. In this work, application of calcium hypochlorite (Ca(ClO)2) and carboxymethyl chitosan (OCMC) as combined depressants for selective flotation separation of chalcopyrite from pyrite was investigated. A maximum recovery difference of 71.35 % between both minerals is observed under the recommended conditions ([Ca(ClO)2] = 60 mg/L, [OCMC] = 400 mg/L and 40 mg/L SBX at pH=8). Besides, the copper-sulfur flotation separation indexes were assessed by the artificial mixed-mineral tests. Results of contact angle measurement, zeta potential and adsorption amount analysis reveal that the combined depressants severely impede the collector adsorption onto pyrite surfaces, and has a light effect on the chalcopyrite. OCMC exhibits a stronger complexing ability on Ca2+ and Fe2+ ions than Cu2+ ions. XPS results confirm that the combined depressant interact with pyrite surfaces intensively, and prompt a deep conversion of S22- and Sn2-/S0 into S2- and SO42- species, as well as a deep transformation of Fe(II)-S into Fe(III)-O/OH on the pyrite surface. ToF-SIMS and thermodynamic calculation results afford the favorable evidence for the selective suppression of the pyrite with added the combined depressant. Thereby the selective oxidation and intense complexation on the pyrite stemming from the combined depressant synergy are responsible for the selective separation of chalcopyrite from pyrite.