Aeromonas hydrophila, an opportunistic bacteria, causes several devastating diseases in humans and animals, particularly aquatic species. Antibiotics have been constrained by the rise of antibiotic resistance caused by drug overuse. Therefore, new strategies are required to prevent appropriate antibiotic inability from antibiotic-resistant strains. Aerolysin is essential forA. hydrophilapathogenesis and has been proposed as a potential target for inventing drugs with anti-virulence properties. It is a unique method of disease prevention in fish to block the quorum-sensing mechanism ofA. hydrophila. In SEM analysis, the crude solvent extracts of both groundnut shells and black gram pods exhibited a reduction of aerolysin formation and biofilm matrix formation by blocking the QS inA. hydrophila. Morphological changes were identified in the extracts treated bacterial cells. Furthermore, in previous studies, 34 ligands were identified with potential antibacterial metabolites from agricultural wastes, groundnut shells, and black gram pods using a literature survey. Twelve potent metabolites showed interactions between aerolysin and metabolites during molecular docking analysis, in that H-Pyran-4-one-2,3 dihydro-3,5 dihydroxy-6-methyl (−5.3 kcal/mol) and 2-Hexyldecanoic acid (−5.2 kcal/mol) showed promising results with potential hydrogen bond interactions with aerolysin. These metabolites showed a better binding affinity with aerolysin for 100 ns in molecular simulation dynamics. These findings point to a novel strategy for developing drugs using metabolites from agricultural wastes that may be feasible pharmacological solutions for treatingA. hydrophilainfections for the betterment of aquaculture.