Nanomaterials (NMs) have settling behavior and accumulate in the benthic area of the aquatic ecosystems. Because of deposit-omnivorous feeding behavior of decapod crustaceans, these order species are appropriate biological models to assay NMs eco-toxicological effects. The present study evaluated the toxicity effects of ZnO and MWCNTs nanomaterials as separately and in combination on antioxidant enzymes activities, CHH hormone, hematology, reproductive performance, and hepatopancreas lesions of the Macrobrachium nipponense. The study was carried out in two stages. At the first experiment, concentrations of ZnO (0, 1, 10, 30, 50 mg/L) and MWCNTs (0, 5, 10, 15, 20 mg/L) were assayed then at the second experiment, two higher concentrations of the NMs in the first stage were compared in combined treatments. The experimental tanks (500 l RAS system) were stocked 12 females and four males during 60 days. Both NMs showed dose-dependent toxicity effects on M. nipponense reproductive parameters and especially eggs fertilization rate. Also, the results depicted that by increasing the NMs concentrations, inter-molt and inter-spawn periods were postponed so that in 50 ppm ZnO and 15 and 50 ppm MWCNTs treatments reproduction activities were stopped. The findings showed that CHH hormone release and superoxide dismutase (SOD) enzyme activity have direct relations to the NMs levels independently and in combination. Also, the results demonstrated that large granular hemocyte (LGH) deal with NMs detoxification in decapod crustacean’s hemolymph mainly. The NMs did not show any effect on ALT and AST enzymes activities in muscle tissue independently, but the NMs combined effects on these enzymes activities were significant. Also, the NMs caused hepatocyte enlargement, melanization, apoptosis, and necrosis damages in the hepatopancreas. The findings showed that ZnO and MWCNTs NMs have strongly adverse effects on M. nipponense, and this species is an appropriate bio-indicator and bio-monitor organism for NMs contaminations in the freshwater aquatic environments.