Dietary polyphenols are very essential and are widely studied compounds due to their various biological activities. The anti-bacterial protein, lysozyme is beneficial for its various biological properties and drug carrying ability. Hence their binding at molecular level is essential perspective in the field of pharmaceutics. The binding of fisetin and morin with chicken egg lysozyme have been investigated using UV–vis, fluorescence, circular dichroism (CD) and molecular docking studies. The polyphenols are found to be the quencher of lysozyme fluorescence and the quenching mode involved here is found static in nature. Moderate binding was observed and fisetin exhibits greater binding affinity (1.63 × 104 M−1) towards lysozyme over morin (1.25 × 104 M−1). The energy transfer parameters are calculated and a possibility of energy transfer from lysozyme to the polyphenols is observed. CD studies reveal that the interactions with the polyphenols induced some structural changes in lysozyme. The polyphenols increased the α-helix percentage of lysozyme during binding. Molecular docking study indicates that the distance of morin towards lysozyme is greater than fisetin. The Program of Energetic Analysis of Receptor Ligand System (PEARLS) has been used to determine the binding energies of the ligands towards lysozyme and the data obtained are in well agreement with docking results.