This study used static bioassay to evaluate oxidative and genotoxic effect caused by ethanolic extract of A. philoxeroides in the liver of C. gariepinus as well as the Histopathological damages caused by the extract on the liver, gills and intestine of the fish. LC50 of the ethanolic extract of A. philoxeroides was determined by probit regression analysis. Fishes were exposed to the sublethal concentration of the extract at the rate of 1% and 10% concentration of the LC50 value in replicate for 21days. During the cause of exposure the fishes exhibited some behavioral changes such as erratic swimming pattern, restlessness and excessive mucus secretion. The oxidative stress study revealed that antioxidant enzyme activities were lower in the liver suggesting deficiency of the antioxidant system to compensate for oxidative stress. DNA damage was high in liver of the exposed fish indicating genotoxic effects. The histological structure of the liver of the fish showed the presence of traces to mild onset of nuclei degeneration. The gills of fish exposed to the extract showed severe collapse of the secondary lamella in conjunction with hyperplasia of the pillar cells within the lamella as well as severe atrophy of the cells, degeneration of the primary lamella and severe cellular and structural damages of the gills. The intestine of the fish group exposed to the extract revealed a small amount of PAS-positively stained substances in the lamina propria, mucus cells and the apical borders of the epithelial cells showing the presence of mucous substances. This study concluded that exposure of C. gariepinus to ethanolic extract of Alternanthera philoxeroides have the ability to negatively affect the behavior, suppress the activities of major antioxidant enzymes of the liver thereby causing oxidative stress, with consequent degeneration of liver and gill tissue which expresses its genotoxicity.