This study investigated the effects of sublethal concentrations of aqueous crude leaf extract of Vernonia amygdalina on oxidative stress biomarkers, liver histopathology, and histomorphometry in juvenile Clarias gariepinus. Juvenile African catfish were exposed to 0.00, 0.40, 0.80, and 1.60 g/L of the extract for 56 days in a static-renewal bioassay system. Liver superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) were determined using standard biochemical procedures. Liver tissues were also examined using routine paraffin-wax processing and haematoxylin and eosin staining, while histomorphometric parameters, including hepatocyte diameter, hepatic cytosurface area, hepatic nuclear surface area, and hepatic surface area, were measured using image analysis software. The results showed a concentration-related reduction in SOD activity, with the lowest value recorded at 1.60 g/L. GPx activity varied significantly among the treatment groups (p < 0.05), whereas the variation in MDA was not statistically significant (p > 0.05). Histological examination revealed normal hepatic architecture in the control fish, mild central venous and sinusoidal congestion at lower concentrations, and moderate sinusoidal congestion with diffuse hepatocellular degeneration at 1.60 g/L. Significant alterations (p < 0.05) were also observed in the measured liver histomorphometric parameters. The findings demonstrate that prolonged exposure to sublethal concentrations of V. amygdalina leaf extract can induce oxidative imbalance and structural alterations in the liver of juvenile C. gariepinus. Therefore, the use of V. amygdalina as a piscicide or pesticide near aquatic ecosystems should be carefully regulated to minimise potential adverse effects on fish health and aquatic biodiversity.