Amyloid depositions of human islet amyloid polypeptides (hIAPP) are associated with type II diabetes (T2D) impacting millions of people globally. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Helix mimetics, which modulate the protein-protein interaction by mimicking the side chain residues of a natural α-helix, were found to be a promising strategy for inhibiting hIAPP aggregation. Here, we applied molecular dynamics simulations to investigate two helix mimetics reported to have opposite effects on hIAPP aggregation in solution, the oligopyridylamide-based scaffold 1e promoted, whereas naphthalimide-appended oligopyridylamide scaffold DM 1 inhibited the aggregation of hIAPP in solution. We found that 1e promoted hIAPP aggregation because of the recruiting effects through binding with the N-termini of hIAPP peptides. In contrast, DM 1 with a higher hydrophobic/hydrophilic ratio effectively inhibited hIAPP aggregation by strongly binding with the C-termini of hIAPP peptides, which competed for the interpeptide contacts between amyloidogenic regions in the C-termini and impaired the fibrillization of hIAPP. Structural analyses revealed that DM 1 formed the core of hIAPP-DM 1 complexes and stabilized the off-pathway oligomers, whereas 1e formed the corona outside the hIAPP-1e complexes and remained active in recruiting free hIAPP peptides. The distinct interaction mechanisms of DM 1 and 1e, together with other reported potent antagonists in the literature, emphasized the effective small molecule-based amyloid inhibitors by disrupting peptide interactions that should reach a balanced hydrophobic/hydrophilic ratio, providing a viable and generic strategy for the rational design of novel anti-amyloid nanomedicine.