The flotation separation of chalcopyrite and galena presents significant challenges due to their similar surface properties, resulting in comparable floatability. In the process of flotation separation, conventional depressants encounter issues related to high toxicity or limited effectiveness. In this paper, it was found that the floatability of galena decreased significantly after pretreatment with potassium peroxymonosulfate (PMS) oxidation. The influence on chalcopyrite, however, is relatively insignificant. In flotation tests of mixed binary minerals, without PMS oxidation, the two minerals are basically floating; When the pH is 8 and the dosage of PMS is 0.375 g/L, it is possible to obtain a flotation concentrate with a Pb grade of 26.78% and recovery of 36.10%, as well as a Cu grade of 21.53% and recovery of 83.66%, when the raw ore contains Pb 44.88% and Cu 15.57%. The oxidation pretreatment method enables the separation of galena and chalcopyrite without the need for a depressant. The XPS and AFM measurements revealed a significantly higher oxidation degree of galena compared to chalcopyrite after treatment with PMS, indicating a notable difference in their floatability. Consequently, the separation of chalcopyrite and galena is greatly facilitated by this distinction. In conclusion, PMS can be considered as a novel oxidant that provides an effective approach for selectively floating chalcopyrite and galena.