One of the major environmental concerns in the mining industry is the generation of acid leachates from tailings deposits, which are highly concentrated in potentially hazardous elements. The continuous processing of these leachates in treatment plant is unsustainable, so the in situ chemical improvement of the mine wastes and their leachates, mainly with another waste produced in the mining area, can reduce treatment and operational costs. This study aimed to evaluate the effect of two types of domestic wastewaters (DWW) on the improvement of the chemical characteristics of the leachates generated from mine wastes containing sulfides. A mesocosm assay was performed under greenhouse and controlled conditions with mine wastes collected in La Zanja mining area (Peru). Three irrigation treatments were tested: untreated DWW, treated DWW and water as control. Percolated leachates of each treatment were collected once per week, for a period of 10 weeks. Electrical conductivity, pH and multi-elemental concentration were analysed. During the assay, the mine wastes generated acid leachates (≈4) with significant concentrations of elements (mg/L; Al: 1.4–30.0; Cd: 0.05–0.19; Cu: 5.7–22.1; Fe: 1.6–19.4; Mn: 2.6–26.0; Zn: 1.2–9.2) and sulfates (204.3–997.8 mg/L), which exceed the thresholds established by Peruvian legislations. After DWW application, pH in the leachates increased to ≈7 and concentrations of several studied elements (e.g. Al, As, Fe, Cu, Zn, Cd, Pb, Ni, Mn) and sulfates decreased (>70% depending on DWW type, element and sampling) compared to the control. This fact allowed that the Environmental Quality standards from Peru (except for Cu and Mn) were reached. However, an enrichment of Na and K was obtained at the same leachates. At short term, the DWW application (especially untreated) on the mine wastes containing sulfides was effective in the improvement of the general chemical quality of their leachates. Moreover, the combined management of these two studied wastes (domestic wastewater and mine wastes) represents a promising cost-effective strategy during mining operation.