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Waterbodies of India support a wide range of molluscs including Lamellidens marginalis , a pearl forming edible mussel of ecological significance. Report of copper oxide nanoparticle toxicity in Indian molluscs is limited in scientific literature. L. marginalis is a gill respiring filter feeder, which is toxicologically vulnerable to exposure of copper oxide nanoparticles liberated from electrical, textile and polymer industries. Experimental exposure of copper oxide nanoparticles for 7 days yielded a decrease in gill filtration rate, respiration rate, total count and phagocytic response of hemocytes, the chief immunoeffector cells of L. marginalis. Nanoparticle exposure resulted in decrease of phagocytic response of mussel hemocytes. Decrease in nitric oxide generation and phenoloxidase activity were recorded in L. marginalis exposed to 0.5, 1 and 5 mg copper oxide nanoparticles per litre of water for 7 and 14 days. Superoxide anion generation in hemocytes was increased under the exposure of copper oxide nanoparticles. Increase in superoxide anion and decrease in the activities of superoxide dismutase and catalase were indicative to oxidative stress in mussels. Copper oxide nanoparticle induced shift in filtration and respiration rate along with the hemocyte associated immune parameters were suggestive to an acute immunophysiological stress in L. marginalis. We estimated the functional performance of gill and physiological status of aquatic respiration in L. marginalis exposed to copper oxide nanoparticles. A parallel set of estimation of each parameter was carried out in L. marginalis exposed to identical copper sulphate concentrations to record and compare the ionic toxicity of copper in the same specimen. Unlabelled Image • Exposure of 0.5, 1, and 5 mg/L of CuONP/7 d yielded decrease in mussel hemocyte count. • CuONP declined filtration rate, respiration rate, phagocytosis, NO and PO activity. • Mussel exposed to CuONP for 7 and 14 d exhibited increased level of superoxide anion. • CuONP induced decrease in superoxide dismutase and catalase activity in hemocytes. • CuONP and copper sulphate exposure caused increase in activities of phosphatases. [ABSTRACT FROM AUTHOR]