The flotation separation of fluorite and calcite poses a long-standing challenge in the mineral processing industry because of their similar physicochemical characteristics. This study uses sodium oleate (NaOL) as the collector and Pb-water glass as the depressant to improve the fluorite-calcite separation efficiency. The effect of Pb-water glass was analyzed using micro-flotation experiments, calculations of solution chemistry, X-ray photoelectron spectroscopy (XPS), zeta potential and time of flight secondary ion mass spectrometry (ToF-SIMS). The results of micro-flotation experiments show that Pb-water glass exhibits a stronger selective depression effect on calcite than water glass alone, but is considerably less sensitive to fluorite flotation. The calculations of solution chemistry, XPS and zeta potential results show that the improved depression effect can be attributed to lead ions, which not only increase the adsorption of silicate species on the calcite surface but also improve the formation of Pb-silicate polymer species. The ToF-SIMS results further show that the adsorption of Pb-water glass on the calcite surface interferes with the adsorption of NaOL on the calcite surface, thereby reducing the floatability of calcite. •Fluorite is difficult to separate from calcite using only a water glass depressant.•Pb(NO3)2 enhances the selective depression effect of water glass on calcite.•The adsorption mechanism of Pb-water glass on the mineral surface is discussed.