The peroxyl radical scavenging activity of five guaiacol derivatives (GD) has been studied in nonpolar and aqueous solutions, using the density functional theory. The studied GD are guaiacol, vanillin, vanillic alcohol, vanillic acid, and eugenol. It was found that the environment plays an important role in the peroxyl scavenging activity of these compounds. They were all found to react faster in aqueous solution than in nonpolar media. The order of reactivity in nonpolar environments was found to be vanillic alcohol > eugenol > guaiacol > vanillin > vanillic acid, while, in aqueous solution, at physiological pH, it becomes vanillic acid > vanillic alcohol > guaiacol ≈ eugenol > vanillin. It was also found that in aqueous solution as the pH increases so does the reactivity of GD toward peroxyl radicals. The environment also has important effects on the relative importance of the hydrogen transfer (HT) and the sequential proton electron transfer (SPET) mechanisms, which are the ones relevant to the peroxyl radical scavenging activity of GD. The HT from the phenolic OH was identified as the main scavenging process in nonpolar media, and in aqueous solution at pH ≤ 4. On the other hand, SPET is proposed to be the one contributing the most to the overall peroxyl scavenging activity of GD in aqueous solution at pH ≥ 6.