This study investigated the influence of mineral oxidation on Cu-Pb separation using green reagent sodium humate as depressant for galena. The flotation tests showed that sodium humate had a poor selectivity when it was used alone, especially with high dosage of sodium humate chalcopyrite could be depressed as well. Long time stirring or the addition of oxidants could significantly enhance the depressant ability of NaHA for galena. Zeta potential, electrochemical, and XPS measurement were conducted, indicating that surface oxidation of galena was conducive to the adsorption of sodium humate and then enhanced its inhibitory ability and selectivity.