The rapid expansion of global aquaculture has heightened the need for efficient health management strategies to combat persistent disease outbreaks and the growing threat of antimicrobial resistance (AMR). Molecular modeling has emerged as a transformative tool in aquatic animal health, offering detailed insights into biomolecular structures and interactions that are otherwise difficult to capture through traditional methods. This chapter presents a comprehensive overview of the principles and applications of molecular modeling techniques such as protein structure prediction, molecular docking, molecular dynamics (MD) simulations, and computer-aided drug design (CADD)—and explores their pivotal role in aquaculture disease diagnostics, therapeutics, and vaccine development. Protein structure prediction, using tools like AlphaFold and I-TASSER, enables researchers to model pathogen and host proteins with high accuracy, facilitating the identification of functional domains and drug targets. Molecular docking and MD simulations further help evaluate ligand binding, predict protein–protein interactions, and assess the stability of complexes, providing a foundation for rational drug design. It has further scope in vaccine development and combating antimicrobial resistance. The molecular modeling has been used for understanding host-pathogen interactions and drug development. Overall, molecular modeling provides a powerful in silico platform that enhances our understanding of aquatic disease pathogenesis and accelerates the development of effective intervention strategies.