In order to selectively separate smithsonite and calcite using potassium lauryl phosphate as collector and reveal the depression mechanism, the approaches of micro-flotation and zeta potential measurements were adopted. The effects of sodium hexametaphosphate (SHMP), water glass (WG), carboxymethyl cellulose (CMC) and lignosulfonate calcium (LSC) as depressants on smithsonite and calcite have been studied through micro-flotation. The single mineral flotation tests show that LSC can depress calcite, but it has little effect on smithsonite flotation. Flotation separation of a mixture of smithsonite and calcite can be completed to obtain a zinc concentrate grade up to 33.85% Zn with a recovery of 70.06%. The zeta potential results illustrate that LSC has higher tendency to be adsorbed on the surface of calcite. However, there is little adsorption of LSC on smithsonite.