Mitochondrial-derived peptides (MDPs) and their analogs have emerged as wide-spectrum, stress response factors protective in amyloid disease models. MDP cytoprotective functions are generally attributed to anti-apoptotic activity, however, little is known about their capacity to facilitate the cell's unfolded protein response via direct interactions with amyloidogenic proteins. Here, we explored the effects of the MDP-analog, humaninS14G (HNG), and the MDP, small humanin-like peptide 2 (SHLP2), on the misfolding of islet amyloid polypeptide (IAPP), a critical pathogenic step in type 2 diabetes mellitus (T2DM). Our thioflavin T fluorescence studies show that HNG inhibits IAPP misfolding at highly substoichiometric concentrations. Seeded fluorescence and co-sedimentation studies demonstrate MDPs block amyloid seeding and directly bind misfolded, seeding-capable IAPP species. Furthermore, our electron paramagnetic resonance spectroscopy and circular dichroism data indicate MDPs do not act by binding IAPP monomers. Taken together our results reveal a novel chaperone-like activity wherein these MDPs specifically target misfolded amyloid seeds to inhibit IAPP misfolding which, along with direct anti-apoptotic activity and beneficial metabolic effects, make HNG and SHLP2 exciting prospects as T2DM therapeutics. These data also suggest that other mitochondrial stress response factors within the MDP family may be amenable to development into therapeutics for protein-misfolding diseases.