Pharmaceutical effluents represent a growing environmental concern, yet studies on the toxicological impacts of treated pharmaceutical wastewater on freshwater fish remain limited, particularly in sub-Saharan Africa. This study investigated the acute toxicity of treated pharmaceutical effluent on Clarias gariepinus (African catfish) and its histopathological effects on gill, liver, and muscle tissues. Effluent samples were collected from a pharmaceutical facility in Ilorin, Nigeria, and tested at concentrations of 12.5%, 25%, 50%, 75%, and 100% (v/v) over 96 hours using a static renewal bioassay (n = 10 fish per concentration group, in duplicate tanks). Physicochemical parameters of the effluent were characterized, and histopathological changes were assessed by haematoxylin and eosin staining. The LC50 was determined as 18.75%, indicating high toxicity even after treatment. Concentration-dependent behavioural disturbances included erratic swimming, frequent surfacing, loss of equilibrium, and lethargy. All fish in concentrations ≥25% died before 96 hours. Histopathological examination revealed significant lesions in gills (epithelial lifting, lamellar swelling, necrosis), liver (vacuolation, portal congestion, fatty degeneration, hepatic cord disruption), and muscle (fibre degeneration, focal necrosis, vacuolar degeneration). Control fish showed no visible lesions. These findings demonstrate that treated pharmaceutical effluents remain acutely toxic to aquatic organisms, with histopathological changes serving as sensitive bioindicators of sub-lethal toxicity. Stricter effluent treatment standards and regulatory oversight are urgently needed to protect aquatic ecosystems and human health.