The current study investigates the hepatotoxic effects of two acute doses of silver nanoparticles (AgNPs) and silver nitrate (AgNO3) on African catfish (Clarias garepinus) using biochemical, histopathological, and histochemical changes and the determination of silver in liver tissue as biomarkers. AgNPs-induced impacts were recorded in some of these characteristics based on their size (20 and 40 nm) and their concentration (10 and 100 μg/L). Concentrations of liver enzymes (Aspartic aminotransferase; AST, Alanine aminotransferase; ALT), alkaline phosphatase (ALP), total lipids (Tl), Glucose (Glu) and Ag-concentration in liver tissue exhibited a significant increase under stress in all exposed groups compared to the control group. The total proteins (Tp), albumin (Al), and globulin (Gl) concentrations exhibited significantly decrease in all treated groups compared to the control group. At tissue and cell levels, histopathological changes were observed. These changes include proliferation of hepatocytes, infiltrations of inflammatory cells, pyknotic nuclei, cytoplasmic vaculation, melanomacrophages aggregation, dilation in the blood vessel, hepatic necrosis, rupture of the wall of the central vein, and apoptotic cells in the liver of AgNPs-exposed fish. As well as the depletion of glycogen content in the liver (feeble magenta coloration) was observed. The size and number of melanomacrophage centers (MMCs) in liver tissue showed highly significant difference in all exposed groups compared to the control group. Recovery period for 15 days led to improved most alterations in the biochemical, histopathological, and histochemical parameters induced by AgNPs and AgNO3. In conclusion, one can assume liver sensitivity of C. garepinus for AgNPs and the recovery period is a must.