Efficient Zn inhibitors are crucial for Pb–Zn flotation separation. In this paper, a novel inhibitor primarily based on sodium thioglycolate (TZ) and lime (CaO) was used. The synergistic effects of the two materials not only improve the inhibition of sphalerite (the primary form of ZnS) flotation but also greatly reduce the required amount of CaO, thereby enhancing the separation of galena (the primary form of PbS) and lowering the overall cost. In the flotation experiments, TZ/CaO effectively reduced the recovery and grade of Zn to 14.68% and 9.32%, respectively. Contact angle measurements, time-of-flight secondary ion mass spectrometry, X-ray photoelectron spectroscopy, and scanning electron microscopy revealed that the combined inhibitor was adsorbed on the surface of sphalerite through synergistic effects, and the -COOH group of the adsorbed TZ enhanced the hydrophilicity of sphalerite, making it difficult to collect. Ultimately, the TZ/CaO combination has strong potential for the industrial flotation separation of sphalerite and galena.