Recently, Cu-based nanoparticles have drawn considerable attention for their various fascinating roles in multiple biological systems. It is recognized that their frequent use can create compatibility challenges for the recipient systems. Nevertheless, it is unclear how various biological interactions affect the compatibility of Cu oxide II (CuO) and Cu oxide nanoparticles (Cu-NPs) for different organisms. Consequently, it has been difficult to perform structured risk assessments for their use in biological systems. Therefore, this study compared the effects of different doses of waterborne Cu-NPs and CuO on the blood and liver of selected groups of Cyprinus (C) carpio. These fish while housed in suitable water tanks were exposed to one of the following treatments for 14 d: control (no added Cu) or 0.5 or 1 or 1.5 mg Cu as Cu-NPs or CuO l-1 of water. We found significant changes in all assessed blood parameters of fish in response to increasing doses from 0 to 1.5 mg of Cu-NPs or CuO. Similarly, increased levels of lipid peroxide and reduced glutathione (GSH) were also observed in the livers of C. carpio in Cu-NPs or CuO treated groups. Enhanced levels of lipid peroxidation and GSH were also recorded in the Cu-NP treated groups compared with the CuO treated groups in a dose dependent manner. The lowest catalase activity was observed in the liver of C. carpio treated with the higer dose of Cu-NPs. Cu-NP or CuO exposure induced significant histological alterations in the liver of C. carpio including focal necrosis, cloudy swelling of hepatocytes, degenerative hepatocytes, vacuolization, pyknotic nuclei, damaged central vein, nuclear hypertrophy, dilated sinusoid, vacuolated degeneration, congestion, and complete degeneration in a dose dependent manner. Substantial alterations in blood and liver specimens were observed in the Cu-NP treated fish when compared with the CuO treated fish. It appeared that the Cu-NPs were more toxic than the CuO as shown by the hemato- and hepatotoxicity in C. carpio of this study.