Diet quality has an important effect on the living organism's physiological biomarkers. This study aimed to investigate the modulation of the immune response and oxidative stress of Clarias gariepinus by the florfenicol (FFC) and nanocurcumin (NCur) as feed additives. Moreover, the ameliorative effects of NCur against FFC toxicity were assessed. Blood and serum biochemical parameters and histopathology of spleen and anterior kidney biopsies were examined after feeding. Four diet variants were formulated and used to feed the fish for 15 successive days, a basal (control), NCur, FFC and FFC combined with NCur. The results revealed that the FFC diet significantly reduced the hematological indices and induced changes in erythrocyte morphology, whereas leucocytes and mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) increased significantly. FFC significantly decreased superoxide dismutase (SOD), glutathione reductase (GSH), catalase (CAT), and immunoglobulin (Ig) levels and significantly increased malondialdehyde (MDA). Combination feeding of NCur and FFC restored some of the hematological changes, immune status, and minimized the oxidative damage induced by FFC. Additionally, it improved the histological aberrations observed in the fish spleen and anterior kidney. The current study revealed that NCur can be utilized as an ameliorative feed to reduce FFC-induced damage in catfish.