2,5-Dimercapto-1,3,4-thiadiazole (DMTD) is an excellent activator of carbonate minerals containing Cu. However, few studies have been conducted on this activation mechanism. In this study, the effects of DMTD modification on the floatability and flotation interface characteristics of azurite and xanthate adsorption were systematically investigated. Micro-flotation tests demonstrated that pretreatment with an appropriate concentration of DMTD in the range of 20–40 mg/L increased the flotation recovery of azurite by 50% when potassium butyl xanthate (KBX) was used as the collector. FESEM-EDS, XPS, UV–Vis, ICP-OES, ToF-SIMS and contact angle analyses demonstrated that DMTD surface modification proceeded through a chemical reaction, resulting in the formation a three-dimensional core–shell structure consisting of a core (azurite) and a shell (Cu(I)-DMTD). Compared to the surface of natural azurite, that of azurite modified with DMTD had an increasing number of Cu active sites, which promoted the effective adsorption of KBX on azurite, thus significantly improving azurite hydrophobicity. The decreased floatability of azurite is closely related to the formation of colloidal Cu(I)-DMTD components in solutions with excess DMTD. This study improves our understanding of DMTD modification and presents a direction for enhancing the xanthate flotation of copper oxide minerals using DMTD as an activator.