Background <p>Cadmium is a highly toxicant heavy metal that poses serious risks to aquatic organisms, animals, and humans. Recent studies have investigated using biological chitosan nanoparticles (Bio-CHNPs) as a potential solution to alleviate the harmful effects of Cd exposure, particularly in aquaculture. Bio-CHNPs have gained attention for their applications in drug delivery and biomedical research, indicating their potential utility in addressing environmental toxicity.</p> Objective <p>This research aims to explore the effectiveness of Bio-CHNPs in mitigating cadmium chloride (CdCL₂) toxicity in African catfish (<i>Clarias gariepinus).</i></p> Methods <p>One hundred and twenty (n = 120) catfish were divided into 4 groups; G1 (control); G2, intoxicated with 10% LC₅₀ of CdCL₂; G3 received 3&#xa0;g/kg of Bio-CNPs; G4, treated with 10% LC₅₀ of CdCL₂ and Bio-CNPs 3&#xa0;g/kg feed.</p> Results <p>CdCl₂ exposure resulted in severe liver, intestine, and kidney damage, which was evidenced by alterations in biochemical parameters, hormonal imbalance, DNA damage, and micronucleus formation. Antioxidant defense mechanisms were compromised, as the activities of Superoxide Dismutase (SOD), Total Antioxidant Capacity (TAC), and Catalase (CAT) were reduced. mRNA expression levels of inflammatory cytokines such as IL-1β, IL-8, and LBP were also significantly elevated following CdCl₂ exposure. Conversely, Bio-CHNPs treatment showed antioxidant and anti-inflammatory effects, greatly lowering the biochemical, genotoxic, and histopathological effects induced by CdCl₂.</p> Conclusion <p>The outcomes of this study are indicative of the potential of Bio-CHNPs as a promising aquaculture feed supplement, with a dual advantage of antagonizing the toxicity of environmental pollutants like Cd and imparting antioxidant and immunomodulatory effects. Bio-CHNP supplementation can be a viable strategy for remedying aquatic environmental heavy metal pollution, with the ultimate safeguarding of human health and ecosystem balance.</p>