Alzheimer's disease (AD) is associated with the aggregation of amyloid-β (Aβ) peptides into toxic prefibrillar aggregates. Recent experiments reported that small organic molecule O4 decreases the concentration of toxic oligomers by promoting fibrillation and thus reduces Aβ toxicity. However, the atomic-level details of O4-Aβ-oligomer interaction are largely unknown. In this work, we studied the structural stability of the fibrillike Aβ(17-42) trimer by performing atomistic molecular dynamics simulations of 1.5 μs in total on the trimer with and without O4. We found that the Aβ(17-42) trimer is unstable without O4, whereas its structural stability is greatly enhanced with O4. Four binding sites were found around residues F20, S26, and M35, namely the central hydrophobic core (CHC) site, the turn site, and two hydrophobic-groove sites. The two hydrophobic grooves near M35 facilitate O4 to bind through hydrophobic interaction and geometry match. The binding of O4 at the CHC site is mostly stabilized by hydrophobic and π-π stacking interactions. Hydrogen-bonding interaction between O4 and S26 plays a role in the binding of O4 to the turn site. Our work reveals the detailed stabilization mechanism of protofibrillar Aβ oligomers by O4 and may provide novel insight into the development of drug candidates against AD.