Staphylococcus aureus remains a major cause of community‑ and hospital‑acquired infections, with its clinical relevance amplified by the emergence of methicillin‑resistant strains (MRSA). Lipoteichoic acid synthase (LtaS), an essential Mn²⁺‑dependent enzyme involved in lipoteichoic acid biosynthesis, represents an attractive but underexplored antibacterial target. While recent virtual screening studies have proposed potential LtaS inhibitors, most emphasize high‑throughput docking with limited mechanistic insight into binding stability. In this study, an integrated in silico workflow combining molecular docking, redocking validation, molecular dynamics (MD) simulations, and ADME profiling was applied to a focused set of 13 bioactive natural compounds with reported anti‑Staphylococcus aureus activity. Docking identified several ligands with favorable binding scores; however, MD simulations revealed pronounced differences in binding behavior. Rigid polyphenolic scaffolds, particularly galangin and rosmarinic acid, retained stable interactions within the Mn²⁺‑dependent catalytic site of LtaS, whereas more flexible phenylpropanoid derivatives rapidly dissociated or adopted nonproductive surface‑binding modes despite favorable docking energies. Analysis of RMSD, RMSF, intermolecular distances, and hydrogen-bond occupancy suggests that higher ligand rigidity may contribute to active-site stabilization and binding persistence. ADME predictions further supported galangin as a promising lead compound with acceptable drug‑likeness and low predicted toxicity. Overall, this work highlights the limitations of docking‑based ranking alone and underscores the importance of MD simulations for identifying true LtaS binders relevant to anti‑MRSA drug discovery.