Oligomeric aggregates of the amyloid-β (Aβ) peptide are believed to be the primary toxic species that initiate events leading to neurodegeneration and cognitive decline in Alzheimer's disease (AD). Small molecules that interfere with Aβ aggregation and/or neurotoxicity are being investigated as potential therapeutics for AD, including naturally occurring polyphenols. We have recently shown that curcumin exerts a neuroprotective effect against Aβ40-induced toxicity on cultured neuronal cells through two possible concerted pathways, ameliorating Aβ oligomer-induced toxicity and inducing the formation of nontoxic Aβ oligomers, both of which involve curcumin binding to Aβ oligomers. To gain molecular-level insights into curcumin's interaction with Aβ oligomers, we use all-atom molecular dynamics (MD) simulations to study the dynamics and energetics of curcumin binding to an Aβ protofibril composed of 24 peptides. Our results show that curcumin binds to specific hydrophobic sites on the protofibril surface and that binding is generally associated with the concomitant complexation of curcumin into dimers, trimers, or tetramers. Curcumin also binds to the protofibril growth axis ends but without complexation. Analysis of the energetics of the binding process revealed that curcumin complexation contributes in an additive fashion to curcumin-Aβ protofibril interactions. Favorable curcumin-protofibril binding is driven by a combination of hydrophobic interactions between curcumin and protofibril, curcumin self-aggregation, and solvation effects. These interactions are likely critical in blocking Aβ oligomer toxicity and inducing the growth of the protofibrils into "off-pathway" wormlike fibrils observed experimentally.