This study was designed to examine the impact of dietary β-1,3-glucan immunomodulatory and mitigating activities against fipronil and lead-induced pollution in African catfish (Clarias gariepinus) culture. Two hundred forty catfish were randomly divided into four equal groups: the first served as a control; the second was supplemented with β-1,3-glucan; the third was exposed to fipronil and lead; and the fourth was exposed to a combination of fipronil, lead, and β-1,3-glucan. The health status, haematological, immunological, and histopathological changes were all evaluated. Swelling on the dorsolateral side, spinal column deviation (scoliosis), sluggish movement, skin bleaching, excessive mucus secretion, significant variations in blood indices-related measures, and a 45% death rate were all observed in the third group. There was also a significant decrease in IL-1, IL-2, IL-6, and IgM concentrations, as well as a down-regulation of their corresponding gene expression. In the spleen, there were notable necrotic foci and hemosiderosis; in the intestine, severe enteritis and mucinous degeneration of the lining epithelium were common pathological findings. Fish treated with β-1,3-glucan alone or in combination with fipronil and lead demonstrated improved physiological activity, blood indices, and elevations in IL-1, IL-2, IL-6, and IgM concentrations, as well as up-regulation in their gene expression in splenic tissues, when compared to the third group. The spleen and intestine had normal histological architecture with 5% mortalities. No fish mortalities were observed in the control and β-1,3-glucan alone treated groups. These findings suggest that β-1,3-glucan could be a promising dietary supplement for catfish health, immunity, and as a fipronil and lead pollutant neutralizer in catfish culture.