The present study is aimed to evaluate the effects of sub-acute toxicity testing of copper sulphate (CuSO4), on behavioural, histological and biochemical changes of the Oreochromis mossambicus (black tilapia) blood tissues. The effects were assessed according to the previous results on sub-acute toxicity test after exposing fish to several concentrations (0.0, 2.5, 5.0, and 10.0 mg/L). The observations of scanning electron microscope, and transmission electron microscope studies revealed severe histopathological changes on the surface and the cellular changes in blood tissues, respectively. The morphological alterations in blood involved irregular structure of red blood cell and blood clot formation. CuSO4 affected the biochemical alteration of the blood cholinesterase also known as serum cholinesterase (ChE). Blood ChE inhibited up to 80% of activity when exposed to 10.0 mg/L CuSO4. The findings from this study can further improve the quality standards of aquaculture industry and the fundamental basis in selecting suitable strains among freshwater fish species to be used as bioindicator.