Copper has toxic effects in fish, whereas the cyanobacterium Spirulina reportedly has protective effects against metal toxicity in various animal species. The current study, therefore, aimed to investigate the prophylactic role of Spirulina platensis against the effects of copper sulfate (CuSO₄) and copper oxide nanoparticles (CuO-NPs) in Nile tilapia (Oreochromis niloticus). Biochemical, antioxidant, erthyron profile and histopathological endpoints were assessed after for 15 days of exposure in five separate treatment groups: (1) fish pre-fed the normal diet (control), (2) fish pre-fed the normal diet and exposed to 15 mg/L of CuSO₄, (3) fish pre-fed the normal diet augmented with 0.25% Spirulina and exposed to 15 mg/L of CuSO₄, (4) fish pre-fed the normal diet and exposed to 15 mg/L of CuO-NPs, and (5) fish pre-fed the normal diet augmented with 0.25% Spirulina and exposed to 15 mg/L CuO-NPs. Exposure to CuSO₄ or CuO-NPs significantly increased superoxide dismutase and catalase activities in fish, as well as serum total protein, glucose, aspartate aminotransferase, alanine aminotransferase, creatinine, and uric acid concentrations. In contrast, most hematological indices in fish significantly decreased after CuSO₄ or CuO-NPs exposure. Moreover, CuSO₄ and CuO-NPs caused a significant increase in the percentage of poikilocytosis and nuclear abnormalities of red blood cells, as well as histopathological changes in the brain, liver, intestine, and kidneys. Importantly, Spirulina supplementation mitigated against physiological disruption caused by CuSO₄ or CuO-NPs.