Three distinct occurrences of Zn–Cu–Pb mineralization (Um Samiuki, Hilgit, and Maaqal) in Neoproterozoic island arcs of the Shadli Metavolcanics Belt, South Eastern Desert, Egypt, have been investigated in this study. The Shadli Metavolcanics Belt erupted in two magmatic cycles, with the Older Um Samiuki Metavolcanics group getting overlain by the Younger Hamamid Metavolcanics (YHM) group. The YHM group is characterized by two distinct cycles of volcanism. The studied deposits are mainly hosted by volcanic and volcaniclastic rocks that belong to the first cycle of the YHM group. The host-rock succession was interpreted to have been formed by back-arc extensional volcanism and was then deformed and metamorphosed to the lower greenschist facies. The relationship between the mineral occurrences and host rocks remains poorly constrained and controversial. We report new field observations, paragenetic data, mineral chemistry analyses, and in situ sulfur isotopes to characterize the sulfide mineralization and to gain insights into its genesis. Two mineralization styles have been identified in these deposits. The first style in the Um Samiuki deposit is expressed by two massive mineralized bodies that are mostly stratiform. It is distinguished by sphalerite, chalcopyrite, pyrite, galena, and Ag-bearing minerals; followed by bornite and covellite in decreasing abundance. Less abundant supergene phases include secondary copper minerals and iron oxyhydroxides. The hydrothermal alteration is characterized by sericitization, chloritization, epidotization, and silicification. The second style represents disseminated and vein-type sulfides mainly encountered in Hilgit and Maaqal occurrences. It is characterized by pyrite with minor sphalerite and chalcopyrite. The δ34SV-CDT values range from + 5.44‰ to + 9.08‰ with an average of + 8.11‰ ±1.1‰ (n = 18) for massive mineralized zones and from − 2.25‰ to + 3.78‰ with an average of + 1.06‰ ±2.3‰ (n = 8) for disseminated and vein sulfides. Such a variation in the sulfur isotope signatures may imply that both mineralization styles were derived from the thermochemical sulfate reduction (TSR) of seawater and leaching of basement lithologies in varying quantities, consistent with Volcanogenic Massive Sulfide (VMS) deposits of back-arc basins. The negative δ34SV-CDT values of some sulfides from the disseminated and vein mineralization may be seen as evidence for magmatic SO2 disproportionation. The studied VMS deposits display a close spatial and genetic association with submarine felsic volcanism of the YHM group, and their temporal distribution corresponds closely with the Mozambique Ocean closure stage of the Pan-African Orogeny.