Amyloid deposition, arising from the fibrillogenesis of proteins in organs and tissues of the body, causes several neurodegenerative disorders. One therapeutic approach is based on the use of polyphenols and their derivatives for suppressing and inhibiting the accumulation of these toxic fibrils in tissues. In the present study, the anti-amyloidogenic activities of bisdemethoxycurcumin (BDMC), a natural polyphenolic compound, and diacetylbisdemethoxycurcumin (DABC), a synthetic derivative of curcumin, on the amyloid fibrillation of hen egg white lysozyme (HEWL) is studied in depth using thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), circular dichroism spectroscopy (CD), molecular docking and Ligplot calculations. The binding parameters such as binding constants and the number of substantive binding sites were obtained experimentally. It could be shown from docking simulation that four hydrogen bonds via the two phenolic OH groups of BDMC and two β-diketone moiety of BDMC are formed with the Asp-101, Trp-63, Asn-59 and Glu-35 of HEWL, whereas, two hydrogen bonds formed via two β-diketone moiety of DABC with Asn-39 and Trp-63 of HEWL. The short Fӧrster's distance (r) between donor and acceptor, the binding constant values and also the nature of interaction, demonstrate strong interaction between these two curcuminoids and lysozyme. According to amyloid fibrillation and binding results, the interaction of BDMC with HEWL is stronger than that of DABC and amyloid fibrillation of HEWL was inhibited more effectively by BDMC than DABC. It can be suggested that the more inhibitory activity of BDMC than DABC is correlated to the stronger interaction of BDMC with HEWL. These natural polyphenolic compounds are thus good candidates for inhibiting of amyloid formation. The inhibitory activities of BDMC and DABC can be used in drug formulation against the dangerous amyloid-related diseases and provide health promotion for organs and tissues of the body.