This work studies the depression of sphalerite and pyrite with a NaCN:ZnSO4 mixture in the selective separation of Pb-Zn by flotation when the blend is enriched with Ag. Given in this paper are an explanation of depression mechanism and the method for optimizing the Pb-Ag recovery. This was done by analyzing the thermodynamics of an aqueous system and evaluating two experimental techniques: flotation kinetic tests and wettability on minerals. The best Pb-Zn separation was observed using a 10:1 mixture molar ratio and coarse-size-particle distribution in the flotation kinetic test (separation 48.24% and lead recovery 83.70%). Wettability measurements and thermodynamic analysis support that free cyanide [CN−] and zinc cyanide species [Zn(CN)3− and Zn(CN)42−] selectively depressed the pyrite and sphalerite, favoring galena floatability. Finally, the silver recovery (argentite associated with pyrite and quartz) is affected by mineralogical association and both, particle-size distribution and mixture molar ratio.