Metal oxide nanoparticles can exert adverse effects on humans and aquatic organisms; however, their toxic mechanisms are still unclear. We investigated the toxic effects and mechanisms of copper oxide, zinc oxide, and nickel oxide nanoparticles in Danio rerio using microarray analysis and the comet assay. Copper oxide nanoparticles were more lethal than the other metal oxide nanoparticles. Gene ontology analysis of genes that were differentially expressed following exposure to all three metal oxide nanoparticles showed that the nanoparticles mainly affected nucleic acid metabolism in the nucleus via alterations in nucleic acid binding. KEGG analysis classified the differentially expressed genes to the genotoxicity-related pathways "cell cycle", "Fanconi anemia", "DNA replication", and "homologous recombination". The toxicity of metal oxide nanoparticles may be related to impairments in DNA synthesis and repair, as well as to increased production of reactive oxygen species.