Fish of Oreochromis niloticus (Linnaeus, 1758) were treated with different concentrations of Enterotoxigenic Escherichia coli (ETEC) as 103-105, 106 -107 and 109-1010 CFU/ml water. The investigation had conducted to detect experimentally the impact of E. coli toxins on Oreochromis niloticus fish throughout cells blood counts (WBCs, RBCs and Platelets), hemoglobin concentration and histopathological changes of muscles. The values of WBCs, RBCs, Platelets and hemoglobin ranged between (90.70 K/ml -7.10 K/ml), (2.00 m/ml - 0.53 m/ml), (21 K/ml - 3 K/ml) and (8.2 G/dl to 2.50 G/dl) for the hematological indices respectively. The concentration of WBCs, RBCs, Platelets and hemoglobin were lower than control in all the experiment phases. Histopathological changes of O. niloticus treated with E. coli included degeneration, necrosis, atrophy and inflammatory infiltration of WBCs. The results revealed mortality of fish in the highest concentration and high incidence of E. coli toxins in the muscles of O. niloticus induced damage in the muscle tissues and may transfer to the human consumer and cause serious illness.