Human adenovirus and norovirus are environmentally stable, non-enveloped viruses that remain major causes of infections worldwide. Despite their clinical significance, effective antiviral therapeutics targeting these pathogens remain limited. Previous in vitro studies demonstrated that the antimicrobial peptides Mel4 and lactoferricin (LFc) possess antiviral activity against adenovirus type 5 (HAdV-5) and murine norovirus type 1 (MNV-1) and do not cause toxicity at their antiviral concentrations to the host mammalian cells. The ID₅₀ of Mel4 was lower than that of LFc. However, although some data indicated that the mode of action was directed at the capsids of these viruses, the molecular basis of the antiviral activity was not fully elucidated. In this study, in silico approaches were employed, such as HDOCK docking and molecular dynamics (MD) simulations, to understand how Mel4 and LFc interact with key capsid proteins. Structural models of Mel4 and LFc were generated using AlphaFold3, and their physicochemical properties were characterised. Docking analyses against the HAdV-5 hexon, penton base, and fibre knob proteins, as well as the MNV-1 VP1 capsid protein, revealed consistently stronger binding affinities for Mel4 compared with LFc. MD simulations (100 ns) further demonstrated that Mel4–capsid complexes exhibited lower root mean square deviation values, reduced interfacial flexibility, and greater structural compactness relative to LFc complexes, indicating stronger and more stable binding over time. Increased solvent accessibility of Mel4 also suggested its greater interaction potential with viral surfaces. Together, these findings provide a detailed mechanistic framework supporting the superior antiviral activity of Mel4 and highlight specific capsid regions that might serve as targets for peptide-based antiviral development. This study has enhanced the understanding of peptide–virus interactions at the molecular level and offers valuable insights for the rational design of next-generation antivirals against environmentally resilient, non-enveloped viruses such as adenovirus and norovirus.