Different activation mechanisms of Cu2+ and Pb2+ in stibnite flotation were studied via microflotation and adsorption capacity tests and density functional theory (DFT). Microflotation experiments indicated that the recovery rate of stibnite flotation with butyl xanthate (BX) was activated 7.82% higher by Pb2+ than Cu2+. The presence of Pb2+ increased the amount of adsorbed BX on the stibnite surface. The results of DFT also suggested stronger activation by Pb2+. Cu2+ activation induced the formation of Cu-S bonds between the double-bonded S1 atom of BX with Cu, resulting in electron gain. Pb2+ activation was followed by the formation of a stable chelating structure between single-bond S1 and double-bond S2 atoms of BX, resulting in electron loss. This system also facilitated dixanthate formation on the mineral surface via interaction between BX and oxygen, thus improving the floatability of stibnite. This study lays a theoretical foundation for the efficient recovery of stibnite.