Enhanced surface photo-oxidation property associated with ZnS in its nanoparticle form induced alterations in the physico-chemical properties of water in a dose dependent manner. Exposure of ZnS nanoparticles in water resulted in depletion of dissolved oxygen content and reduction in pH value of water significantly. This observation was more prominent for ZnS nanoparticles with smaller sizes. When exposed to ZnS nanoparticles, both the fish species Labeo bata and Mystus vittatus, responded to hypoxia with varied behavioural, physiological and cellular responses in order to maintain homeostasis and organ function in an oxygen-depleted environment. Due to the minimization of food uptake, the hepatic cells of both the fish were found to shrink and empty spaces generated in between them as they used storage deposit to maintain the metabolic activity of the fish. However, the change in hepatic tissue layout was more noteworthy in case of L. bata. The kidneys of both the exposed fish species showed shrinkage of glomerulus and dilution of tubular lumen due to reduction in glomerular filtration rate in oxygen depleted atmosphere. Vacuolization and hyaline degeneration of tubular epithelium were also seen in the renal histomorphology of both the fish when the exposure time exceeded 6 days. Again in this case, the alterations in renal histomorphology were more rapid and distinguishable in case of L. bata. Both the fish species showed prominent alterations in their gill histomorphology displaying dissociation of gill epithelium layer, lamellae fusion, lamellae curling, angiogenesis, vasodilation and disruption of filament and lamellae when they face dose dependent ZnS nanoparticle induced hypoxia and environmental acidification in their habitat. The size and dose dependent changes in gill tissue layout were noticed to be more severe in the case of L. bata compared to M. vittatus. These observations suggest that the species L. bata is more vulnerable compared to the species M. vittatus against ZnS nanoparticle exposure when vital organs like liver, kidney and gills are concerned.