Reactions of sesamol with different free radicals, in lipid and aqueous media, have been studied at the M05-2X/6-311+G(d,p) level of theory in conjunction with the SMD continuum model. Different mechanisms of reaction have been considered as well as polar and nonpolar environments. According to the overall rate coefficients, sesamol is predicted to react significantly faster in aqueous solution than in nonpolar media. The polarity of the environment also changes the relative importance of the reaction mechanisms. The anionic form of sesamol was found to be particularly reactive toward peroxyl radicals by transferring one electron. This mechanism was found responsible for the exceptional peroxyl radical scavenging activity of sesamol in aqueous solution, which was found to be even better than carotenoids, 2-propenesulfenic acid, and glutathione under physiological conditions. The agreement between experimental and calculated data supports the presented results as well as the methodology used in this work.