Many neurodegenerative disorders are induced by protein conformational change. Prion diseases are characterized by protein conformational conversion from a normal cellular form (PrP(C)) to an abnormal scrapie isoform (PrP(Sc)). PrP106-126 is an accepted model for studying the characteristics of PrP(Sc) because they share many biological and physiochemical properties. To understand how metal complexes affect the property of the prion peptide, the present work investigated interactions between Pd complexes and PrP106-126 based on our previous research using Pt and Au complexes to target the peptide. The selected compounds (Pd(phen)Cl(2), Pd(bipy)Cl(2), and Pd(en)Cl(2)) showed strong binding affinity to PrP106-126 and affected the conformation and aggregation of this active peptide in a different binding mode. Our results indicate that it may be the metal ligand-induced spatial effect rather the binding affinity that contributes to better inhibition on peptide aggregation. This finding would prove valuable in helping design and develop novel metallodrugs against prion diseases.