The neurodegenerative disorder Alzheimer's disease (AD) is associated with the accumulation of misfolded proteins. Some recent studies suggested that amyloid beta (Aβ) forms soluble oligomers, protofibrils, and fibrils; the Aβ oligomers being more toxic than the fibrils. Surprisingly, these Aβ oligomers reportedly bind to prion protein (PrP), which acts as a receptor on the cell membrane, possibly resulting in AD. Thus, it is thought that compounds that can disrupt the formation of the prion‐Aβ oligomer complex may prevent AD. Here, we demonstrate that an anti‐prion RNA aptamer, R12, inhibits the interaction of PrP with Aβ. Fluorescence assaying involving thioflavin S showed that wild‐type PrP, a mutant of the N‐terminal half of PrP, and even fragment peptides of PrP effectively inhibit Aβ fibrillization. Fluorescence anisotropy revealed that R12 is capable of binding to PrP, resulting in dissociation of PrP with Aβ. Consequently, the Aβ that dissociated from PrP was shown to polymerize into fibrils. These spectroscopic observations were visualized by transmission electron microscopy. This is the first demonstration of the PrP‐Aβ interaction being disrupted by a nucleic acid. This ability of R12 highlights its therapeutic potential for treating AD pathology.