In Pb-Zn ore flotation, unintentional activation of sphalerite often leads to difficult separation of Pb and Zn minerals, during which grinding plays a key role in unintentional activation. Therefore, the aim of this study was to evaluate the surface component changes of two different mineral particles and to propose the interaction between galena and sphalerite during mixed grinding using time-of-flight secondary ion mass spectrometry (ToF-SIMS). The results show that after mixed grinding of the galena and sphalerite, the Pb content on the sphalerite surface increased with the decrease of Zn and Fe contents on the sphalerite surface. The lead ions from galena were obviously absorbed onto the sphalerite surface, while the zinc and iron ions from sphalerite were not obviously migrated to the galena surface. Principal component analysis (PCA) of a dataset composed of 206 positive ion peaks of galena and sphalerite indicates that the surface components of galena and sphalerite migrated from either side to different degrees. This study successfully identified an important factor for unintentional activation of lead and zinc minerals during flotation: homogenization of surface components of different minerals during grinding.