Phytochemicals and essential oils have been widely used as growth promoters in aquaculture. However, the optimal dose of a blend of essential oils for promoting the growth and health of African catfish (Clarias gariepinus) remains largely unknown. Therefore, the present study aimed to assess the dose-response effects of dietary supplementation with a blend of clove and peppermint oils (CPO) on growth indices, feed utilization, physio-metabolic responses, immunity, and organ histology in African catfish. Catfish (105.1 ± 0.5 g) were fed diets containing 0.0 (control; CPO0), 1.0 (CPO1), 2.0 (CPO2), or 3.0 mL CPO/kg diet for two months. The results displayed that fish performance and feed intake significantly improved with increasing CPO levels in a linear manner (P < 0.01). Additionally, the specific growth rate and hemoglobin (R2 = 84.6%) levels showed quadratic improvements with the optimal doses at 1.12 mL and 1.6 mL/kg diet, respectively. The inclusion of dietary CPO linearly affected aspartate aminotransferase (AST; R2 = 93.1%), alanine aminotransferase (ALT; R2 = 97.7%), alkaline phosphatase (ALP; R2 = 97.0%), and glucose (R2 = 85.9%) levels in the plasma of catfish (P < 0.001). Increasing the concentrations of dietary CPO led to a quadratic decrease in creatinine (R2 = 98.7%), uric acid (R2 = 94.8%), and cortisol (R2 = 87.1%; P < 0.001), with optimal doses confirmed at 1.75, 2.7, and 1.3-mL CPO per kg of diet, respectively. Dietary CPO has a significant modulatory impact on immune-antioxidant variables in African catfish in a dose-dependent manner. Increasing CPO in the fish diets resulted in a quadratic increase in the levels of immunoglobulin G (IgG; R2 = 98.8%), lysozyme activity (R2 = 93.9%), and total antioxidant capacity (R2 = 84.9%). The corresponding dose–response curves displayed that the optimal doses were at 1.85, 2.1, and 1.8 mL/kg of diet. Furthermore, superoxide dismutase (SOD), and reduced glutathione (GSH) levels were significantly improved in all CPO-treated groups in a quadratic manner, with optimal doses at 1.25 mL (R2 = 90.6%) and 1.55 mL (R2 = 89.7%) per kg of diet. Catfish fed diets supplemented with CPO showed gradual improvements in hepatocytes (HP), and blood vessels (BV) with an increased number of binucleated cells. Moreover, catfish fed diets containing CPO had improvement in the tubular epithelium, Bowman’s capsule, and a few melanomacrophage areas. This study revealed that CPO supplementation at an optimal dose of 1–2 mL/kg of diet significantly improved growth performance, feed utilization, metabolic processes, and immune and antioxidant functions in African catfish.