Microplastics (MPs) pollution poses a significant threat to aquatic ecosystems by compromising fish immune function. This study investigates the role of somatostatin (SS) in alleviating MPs-induced immunosuppression in red tilapia. Bioinformatic analysis predicted SS's interaction with immune and apoptotic pathways via receptors like SSTRs and GPR183b. Experimental exposure to different sized MPs (0.1 μm, 1 μm, 10 μm) revealed size dependent tissue accumulation, with 0.1 μm MPs showing significant enrichment in immune organs. MPs exposure induced liver damage (increased activities of ALT and AST) and dysregulated immune gene expression (such as il-8, nf-κB, tgf-β, tnf-α). SS supplementation, particularly at 0.6%, effectively reversed these effects, normalizing serum biomarkers and restoring immune gene expression towards baseline levels. This study reveals the key protective role of SS in alleviating the immunotoxicity of microplastics, providing new ideas for the prevention and control of pollutants in aquaculture.