More research is needed to understand the interactions of nanoparticles (NPs) with aquatic organisms and their mechanism of toxic action. Zinc oxide nanoparticles (ZnONPs) are the most used engineered metal oxide NPs in consumer products. The present study was designed to evaluate the cytotoxicity, genotoxicity and digestive gland (DG) as well as gill histopathology of the freshwater molluscan bivalve Coelatura aegyptiaca following exposure to ZnONPs (2, 10 and 50 mg/L) for 6 consecutive days. Exposure to ZnONPs (10 and 50 mg/L) induced a significant increase in malondialdehyde, superoxide dismutase and nitric oxide with a concomitant decrease in reduced glutathione, glutathione-S-transferase and catalase levels in the haemolymph, DG and gills of the treated mussels. Following exposure to ZnONPs (50 mg/L), the DG exhibited gradual changes in glandular activity showing hypertrophy and hyperplasia in the glandular cells and irregularity of lamellae and swelling of filaments in the gills. The present investigation revealed that oxidative stress induction, genotoxicity in the haemocytes and histological alterations in the DG and gills of C. aegyptiaca could be the main mechanisms involved in ZnONPs toxicity in aquatic organisms. Thereby, it is suggested that ZnONPs should be applied with more precautions in relevant industries, and occupational health surveillance should be necessarily considered.