Poor water solubility and low bioavailability are considered as two main factors restricting therapeutic applications of natural polyphenols in relation to various disorders including amyloid-related diseases. Among various strategies developed to overcome these limitations, nanonization has attracted considerable attention. Herein, we compared the potency of bulk and nano forms of the polyphenolic fraction of pomegranate seed (PFPS) for modulating Hen Egg White Lysozyme (HEWL) amyloid fibril formation. Prepared PFPS nanosheets using direct oxidative pyrolysis were characterized by employing a range of spectroscopic and microscopic techniques. We found that the nano form can inhibit the assembly process and disintegrate preformed fibrils of HEWL much more effective than the bulk form of PFPS. Moreover, MTT-based cell viability and hemolysis assays showed the capacity of both bulk and nano forms of PFPS in attenuating HEWL amyloid fibril-induced toxicity, where the nano form was more effective. On the basis of thioflavin T results, a delay in the initiation of amyloid fibril assembly of HEWL appears to be the mechanism of action of PFPS nanosheets. We suggest that the improved efficiency of PFPS nanosheets in modulating the HEWL fibrillation process may be attributed to their increased surface area in accord with the surface-assistance model. Our results may present polyphenol-based nanosheets as a powerful approach for drug design against amyloid-related diseases.