Nanomaterials (NMs) mainly settle on bottom sediments and accumulate in the benthos of aquatic communities. Decapod crustaceans, being deposit-omnivorous feeders, are appropriate biological models to assay the biological effects of NMs. The present study evaluated the effects of ZnO and multi-walled carbon nanotubes (MWCNTs) NMs separately and in combination on the activities of antioxidant enzymes on crustacean hyperglycemic hormone (CHH), hematology, reproductive performance, and hepatopancreas lesions the Oriental river prawn, Macrobrachium nipponense De Haan, 1849 [De Haan, 1833–1850]. We essayed concentrations of ZnO (0, 1, 10, 30, 50 mg l–1) and MWCNTs (0, 5, 10, 15, 20 mg l–1) and two higher concentrations of the NMs were compared in combined treatments. Both NMs showed dose-dependent effects on reproductive parameters of M. nipponense, especially the fertilization rate of eggs. Inter-molt and inter-spawn periods were postponed and reproduction stopped in 50 ppm ZnO and 15 and 20 ppm MWCNTs treatments. Our findings showed that the release of crustacean hyperglycemic hormone (CHH) and superoxide dismutase (SOD) enzyme activity are directly related to the NMs levels independently as well as in combination. NMs did not show any effect on the activities of alanine transaminase (ALT) and aspartate transaminase (AST) enzymes in muscle tissue independently, but the combined effects of the activities of these enzymes were significant. NMs caused hepatocyte enlargement, melanization, apoptosis, and necrosis damages in the hepatopancreas of prawns. The findings showed that ZnO and MWCNTs NMs have strong adverse biological effects on M. nipponense, and that this species is an appropriate bio-indicator and bio-monitor organism for NMs contaminations in the freshwater aquatic environments.