When valuable digenite is heavily oxidized, it may not respond to the flotation process and remain largely in the tailing with the pyrite. This is problematic because the recovery of digenite from heavily oxidized Cu-S ore is of great significance. In this study, the effect of sodium sulfide on the selective flotation separation of heavily oxidized digenite and pyrite was investigated. The micro-flotation results showed that the floatability of digenite could be effectively restored with the addition of sodium sulfide and sodium butyl xanthate (SBX). However, pyrite showed a poor floatability under the same conditions. Based on this, the flotation separation of artificially mixed minerals was carried out, and a satisfactory result with 51.4% Cu grade and 93.1% Cu recovery could be obtained in the optimized flotation conditions. Then, the sulfidization mechanism of heavily oxidized digenite was discussed in detail through an examination of zeta potential measurements, adsorption measurements, contact angle measurements, and X-ray photoelectron spectroscopy (XPS) analyses. The results indicated that the negatively charged SH- could adsorb on the surface of digenite through chemisorption, and lower the quantity of hydrophilic copper sulfate and oxides/hydroxides on the digenite surface in the presence of SBX, thus significantly increasing the surface contact angle, decreasing the amount of SBX adsorbed to the value observed for unoxidized digenite, and promoting the flotation of heavily oxidized digenite.