• IDS selectively selectively depressed zinc ions activated quartz, which achieved excellent Zn-Si separatetion results. • IDS impeded the adsorption of NaOl on the surface of Zn-Quartz. • The active zinc sites on the surface of Zn-Quartz were chelated and desorbed by IDS. The inevitable presence of zinc ions will increase the difficulty of removing quartz from zinc oxide ores using sodium oleate (NaOl) as a collector. The problem of separating smithsonite from zinc ions activated quartz (Zn-Quartz) is still unresolved. In this study, a readily biodegradable and environmentally friendly reagent (tetrasodium iminodisuccinate, IDS) was introduced for efficiently separating them. Micro-flotation tests showed that IDS could selectively reduce the floatability of Zn-Quartz but barely influence that of smithsonite, and efficient separation of smithsonite from Zn-Quartz was realized. Zeta potential measurements demonstrated that the introduction of IDS prevented the adsorption of NaOl on the surface of Zn-Quartz, while had negligible interference on that of smithsonite surface. Furthermore, inductively coupled plasma optical emission spectroscopy (ICP-OES) and X-ray photoelectron spectroscopy (XPS) were used to further investigate the depressant mechanism of IDS on Zn-Quartz. The results illustrated that IDS could chemically react with zinc sites and desorb them from the surfaces of quartz, thereby depress the flotation of quartz.