Amyloid-beta (A beta) and metal ions are suggested to be involved in the pathogenesis of Alzheimer's disease (AD). Cu(II) and Zn(II) can interact with A beta and facilitate peptide aggregation producing toxic oligomeric peptide species. Additionally, redox-active metal-bound A beta is shown to generate reactive oxygen species (ROS). Although the interaction of metal ions with A beta and the reactivity of metal-associated A beta (metal-A beta) are indicated, the relationship between metal-A beta and AD etiology is still unclear. Some naturally occurring flavonoids capable of redirecting metal-A beta peptides into nontoxic, off-pathway A beta aggregates have been presented as valuable tools for elucidating the role of metal-A beta in AD. The structural moieties of the flavonoids responsible for their reactivity toward metal-A beta are not identified, however. To determine a structure-interaction-reactivity relationship between flavonoids and metal-free A beta or metal-A beta, four flavonoids (morin, quercetin, galangin, and luteolin) were rationally selected based on structural variations (i.e., number and position of hydroxyl groups). These four flavonoids could noticeably modulate metal-A beta aggregation over metal-free analogue to different extents. Moreover, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) studies reveal that the direct interactions of the flavonoids with metal-free and/or metal-bound A beta are distinct. Overall, our studies demonstrate that alternation of the hydroxyl groups on the B and C rings of flavonoids (structure) could differentiate their metal/metal-free A beta/metal-A beta interactions (interaction) and subsequently direct their effects on metal-free A beta and metal-A beta aggregation in vitro and A beta-/metal-A beta-triggered toxicity in living cells (reactivity), suggesting a structure-interaction-reactivity relationship.