A better understanding of the abnormal protein aggregation and the effect of anti-aggregation agents on the fibrillation pathways and the secondary structure of aggregates can determine strategies for the early treatment of dementia. Herein, we present a combination of experimental and theoretical studies providing new insights into the influence of the anti-aggregation drug bexarotene on the secondary structure of individual amyloid-β aggregates and its primary aggregation. The molecular rearrangements and the spatial distribution of β-sheets within individual aggregates were monitored at the nanoscale with infrared nanospectroscopy. We observed that bexarotene limits the parallel β-sheets formation, known to be highly abundant in fibrils at later phases of the amyloid-β aggregation composed of in-register cross-β structure. Moreover, we applied molecular dynamics to provide molecular-level insights into the investigated system. Both theoretical and experimental results revealed that bexarotene slows down the protein aggregation process via steric effects, largely prohibiting the antiparallel to parallel β-sheet rearrangement. We also found that bexarotene interacts not only via the single hydrogen bond formation with the peptide backbone but also with the amino acid side residue via a hydrophobic effect. The studied model of the drug-amyloid-β interaction contributes to a better understanding of the inhibition mechanism of the amyloid-β aggregation by the small molecule drugs. However, our nanoscale findings need to meet in vivo research requiring different analytical approaches.