In this study, the mechanism of the interactions between sesamol and myosin was explored to confirm the potential application of sesamol in a meat protein system. A series of sesamol and myosin solutions were prepared for spectroscopic studies. UV–vis spectroscopy revealed that sesamol formed a complex with myosin and affected the myosin microenvironment. Fourier transform infrared spectroscopy showed that hydrogen bonding was involved in the formation of the complex. Static quenching (Kq = 1.044 × 1012 m−1s−1) of sesamol on myosin and the good binding effect (Ka = 1.44 × 105 L/mol, n = 1.33) between sesamol and myosin were verified by the fluorescence quenching mechanism. Circular dichroism spectroscopy confirmed that the interactions resulted in a decrease of myosin α-helix content. Furthermore, the best pose for successfully docking sesamol with myosin (lowest binding affinity of −6.2 kcal/mol) was shown by molecular docking. The molecular dynamics simulation and small-angle X-ray scattering results determined that hydrophobic interactions and hydrogen bonding allowed the protein structure to be more compact and stabilized. Several key residues (Glu-477, Cys-480, Ile-481, Glu-272, Leu-271, and Leu-270) and a protein residue (Lys-273) formed a structurally stable complex with sesamol through hydrophobic interactions and hydrogen bonding (3.28 Å). The surface hydrophobicity of the sesamol-myosin complex was reduced, solubility and emulsification properties were improved, and a smaller particle size was produced.