<p>Polyphenols are naturally occurring bioactive compounds derived from plants, possessing antioxidant, anti-inflammatory, and immune-modulatory properties. In Whiteleg shrimp (<i>Penaeus vannamei</i>), these compounds bind to beta-1,3-glucan-binding protein (β-GBP), thereby activating crucial immune pathways, including the prophenoloxidase (proPO) cascade. This interaction enhances the activity of antioxidant enzymes, promotes immune homeostasis, and facilitates the scavenging of reactive oxygen species (ROS), ultimately reducing oxidative stress and improving the health, growth, and production of shrimp in aquaculture. In this study, molecular docking was performed on a library of 10,000 phytochemicals to identify potential β-GBP ligands with high binding affinity. From this screening, ten compounds were selected based on their strong binding interactions with β-GBP. Among them, Curcumin and Gingerol emerged as top candidates, with docking scores of − 8.34 kcal/mol and − 8.12 kcal/mol, respectively, and low RMSD values (1.12 and 1.26), indicating stable and accurate binding. Molecular dynamics simulations (MDS) further validated the stability and sustained interactions of these polyphenols-β-GBP complexes over time. Furthermore, the screened polyphenols demonstrated favorable pharmacokinetic profiles, including non-toxicity, non-carcinogenicity, and high gastrointestinal absorption, making them ideal candidates as feed additives in shrimp aquaculture. The modulation of β-GBP pathways by polyphenols not only enhances immune responses but also mitigates oxidative stress, promoting better growth and higher production. These findings suggest that polyphenol supplementation could serve as a cost-effective, sustainable, and eco-friendly strategy to improve shrimp health and productivity to address challenges in aquaculture management. Future studies are recommended to validate these findings into practical applications via in vivo validation, dose optimization, and long-term effects.</p>