HE immunological effects of metal nanoparticles (MNPs) on aquatic animals may be particularly significant since these animals can experience continual exposure to these MNPs dispersed in water throughout their whole life cycle. Chlorella vulgaris (ChV) is commonly used in aquaculture and has various biological and therapeutic characteristics. A total of 144 Nile tilapia (Oreochromis niloticus) were equally categorized into four groups as follows: Control (C), ChV (30 g/kg diet), CuO-NPs (5.72 µg L−1 1/10 LC50), and CuO-NPs/ ChV groups. Our data demonstrated that exposure to CuO-NPs significantly decreased RBCs count, haemoglobin content and heterophile %. On the other hand, exposure to CuO-NPs induced a significant increase in WBC count and lymphocyte %. The exposed fish revealed a significant (P value < 0.05) decrease in phagocytic percent and phagocytic index and a decline in IgM, lysozyme and nitric oxide serum levels. Meanwhile, the INF–γ serum level significantly (P value < 0.05) increased. The RT-PCR analysis demonstrated an up-regulation of NF-𝜅β, TNF-α, IL-1B and TGF-b expression levels. Interestingly, ChV markedly ameliorated against CuO-NPs-induced immunotoxic impairments in fish group-fed diets supplemented with ChV. Our data revealed the immune-protective properties of ChV in CuO-NPs-exposed fish, demonstrating the possible usefulness of ChV as an eventual immune-protective agent.