Zinc oxide nanoparticles (ZnO NPs) are increasingly used in various products as coating and additive materials for household goods, personal-care products, and drug delivery systems. Because of their broad applications, the potential risks to nontarget organisms associated with their input into aquatic environments have generated much concern. We investigated the acute toxicity, morphological responses, and potential impact on physiology and metabolism in polyps exposed to spherical ZnO NPs of either 20 nm (ZnO NP) or 100 nm (ZnO NP). The median lethal concentrations (LC) of ZnO NP were 55.3, 8.7, and 7.0 μg/mL after exposure for 48, 72, and 96 h, respectively; and those of ZnO NP were 262.0, 14.9, and 9.9 μg/mL, respectively. The morphological responses of the hydra polyps to a range of ZnO NP concentrations suggest that ZnO NPs may negatively affect neurotransmission in Hydra. ZnO NPs may also induce abnormal regeneration in the polyps by affecting the expression of several genes related to the Wnt signaling pathway. The presence of ZnO NP in the hydra tissue was confirmed with electron microscopy. A Gene Ontology analysis of the genes differentially expressed in hydra polyps after exposure to ZnO NP for 12 or 24 h revealed changes in various processes, including cellular and metabolic process, stress response, developmental process, and signaling. A KEGG pathway analysis of hydra polyps after exposure of ZnO NP or ZnO NP for 12 or 24 h demonstrated various changes, including in the DNA replication and repair, endocytosis, lysosomes, Wnt signaling, and natural killer-cell-mediated cytotoxicity pathways, suggesting the mechanisms that maintain cellular homeostasis in response to ZnO NPs. Progesterone-mediated oocyte maturation was also affected by the ZnO NPs nanoparticles, suggesting that they are potential endocrine disruptors. This study should increase our concern regarding the dispersal of ZnO NPs in aquatic environments.