Background: Water pollutants cause adverse effects in aquatic ecosystems. The immunomodulatory and mitigating effects of dietary 1,3-glucan on fipronil and lead-induced intoxication in African catfish (Clarias gariepinus) were investigated. Two hundred forty catfish were randomly divided into four equal groups: those in the first group were fed basic diet and served as controls; those in the second group were supplemented with β-1,3-glucan (0.1%); those in the third group were exposed to combination of lead nitrate at 0.041 mg/L (1/10 96 h LC50) and fipronil at 2.8 mg/l (1/10 96 h LC50); and those in the fourth group were exposed to combination of fipronil, lead, and β-1,3-glucan. The health status, haematological, immunological, and histological changes were all evaluated. Result: Swelling on the dorsolateral side, spinal column deviation, sluggish movement, skin bleaching, excessive mucus secretion, significant variations in blood indices-related measures, and a 45% death rate were observed in the third group. There was a significant reduction in interleukin-1 (IL-1) and interleukin-6 (IL-6) and immunoglobulin M (IgM) concentrations, as well as decrease in their corresponding gene expression, indicating that fipronil and lead had immunosuppressive activity. Severe catarrhal enteritis and mucinous degeneration of the lining epithelium, and notable depletion of white pulp, congested red pulp and hemosiderosis were common pathological findings in the spleen. β-1,3-glucan alone or in combination with fipronil and lead provoked physical activity, blood indices, with elevations in IL-1β, IL-2, IL-6, and IgM concentrations, as well as up-regulation in their genes' expression in splenic tissues, when compared to the third group. The spleen and intestine had normal histological architecture with 5% mortalities. There were no fish deaths in the β-1,3-glucan-alone or control groups. Conclusion: The use of β-1,3-glucan (0.1%) as dietary supplement could be implemented to protect against the toxic effects of fipronil and lead toxicity by improving the health and immunological parameters of intoxicated catfish.