Adulteration of aquafeed has raised critical concern regarding quality and safety of aquatic meats. This study assessed the impact of melamine (MEL) and melamine‐formaldehyde (MEF) chemicals (adulterants) on haematology, gill and liver antioxidant enzymes activities of Clarias gariepinus. Fish were fed diets contaminated with MEL and MEF at 3.0 g Kg−1 (0.3%) dietary inclusion for 45 days, followed by a depuration trial that lasted for 30 days. Body biomass of MEL‐ and MEF‐treated groups decreased markedly, relative to the control. Haematological parameters such as red blood cell, white blood cell, haemoglobin and packed cell volume contents of the treated groups reduced prominently, while antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) activities were suppressed, particularly in the liver of the treated groups. Additionally, toxicity of MEL and MEF caused significant increase in malondialdehyde (MDA) content in the gill and liver tissues of the exposed groups. However, antioxidant enzymes activities and haematology were restored to the normal physiological condition, during the recovery (depuration) phase. MEL‐ and MEF‐induced toxic effects on the exposed fish and the findings of the current study provides baseline information and insight on the adverse impact of these chemicals in aquatic models.