Introduction: Histopathological effects of ethanol extract of Adenium obesum stem bark on the liver of Clarias gariepinus was investigated over a 96-h exposure period as an effective organic piscicide. Materials and Methods: An acute static toxicity bioassay was performed after a preliminary concentration range finding test was conducted. Results: Exposed fish showed adaptation behavioural changes with those of respiratory distress and abnormal nervous signs of toxicity, which was concentration-dependent. Mortality was recorded in some of the exposed fish while a median lethal concentration of 7.15 mgL -1 was established for the extract in the exposed fish. Non-significant (p>0.05) changes were recorded in serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activities of the exposed fish. Moderate liver damage was observed in the exposed fish based on the degree of tissue change (DTC) grading where significant (p<0.05) differences were observed between the DTC of the exposed groups and the control. Conclusion: Ethanol extract of A. obesum stem bark was toxic to the exposed fish with evidence of hepatotoxicity and therefore, can be used to eradicate the hardy C. gariepinus from aquatic environments.