The Mehdiabad Zn-Pb-Ba (Cu-Ag) deposit in the southern Yazd Basin, central Iran, is the largest sediment-hosted Zn-Pb deposit in Iran. This deposit is hosted by organic carbon matter-rich shale, fine-grained black siltstone, and dolomite interlayered with sandstone of the Taft Formation. Sedimentological and geochemical studies of the Taft Formation have shown that these organic carbon matter-rich shales formed during a period of basin deepening and under anoxic conditions. Based on the orebody structure, mineralogy, and ore fabrics, we recognize five different ore facies types in the Mehdiabad deposit: (1) a stockwork/feeder zone, consisting of a discordant sulfide mineralization, forming a stockwork of sulfide-bearing dolomite veins, cutting the sedimentary rocks of the footwall; (2) massive-replacement ore, including pervasive replacement carbonate by pyrite, chalcopyrite, galena, and sphalerite with minor barite; (3) a bedded ore, with laminated to disseminated pyrite, sphalerite, and galena; (4) barite ore, which contains accessory sulfide minerals and rare calcite at the top of the deposit, and (5) a distal facies, with minor disseminated and laminated pyrite, banded cherts, and disseminated barite. Two stages of base metal sulfide replacement have separate origins. Fine-grained sulfide bands (stage I), intricately interlayered with organic carbon-rich beds and thin turbidite beds, exhibit lamina and bedding textures, supporting a syn-sedimentary (onto the sea floor) origin. Coarse-grained base metal sulfides (stage II), occurring within breccias and veins to veinlets are considered to have formed by replacement during post sedimentation sub-seafloor fluid flow. δ34S values of pyrite, sphalerite chalcopyrite and galena range from −22 to +4.6.8‰. The highest δ34S values correspond to the feeder zone (+4.6 and −10.5‰), whereas massive-replacement (+3.7 to −13.7‰) and bedded (−22 to −17‰) ore facies display depleted compositions. The overall range of δ34S values is remarkably higher than typical magmatic values, suggesting that sulfides formed from the reduction of seawater sulfate by bacteriogenic sulfate reduction in a closed or semi-closed system in the bedded ore, whereas thermochemical sulfate reduction likely played an important role in the feeder zone. The formation of the Mehdiabad deposit follows the evolution of the sedimentary basin. Abrupt lateral changes in facies and thickness, along with the existence of synsedimentary breccias and debris flows within the ore sequence, suggest the proximity to synsedimentary faults and tectonic activity contemporaneous with the sedimentation in the Lower Cretaceous, favorable for the formation of the ore deposit. The deposit formed from a combination of hydrothermal and syn-sedimentary processes. Sulfur isotopes, together with sedimentological, textural, mineralogical, and geochemical evidences, suggest that this deposit should be classified as a vent-proximal sub-seafloor replacement SEDEX ore deposit.