Density functional theory was employed to highlight the antioxidant working mechanism of higenamine in aqueous and lipid-like environments. Different reaction mechanisms were considered for the reaction of higenamine with the •OOH radical. The pH values and the molar fraction at physiological pH were determined in aqueous solution. The results show that the preferred reaction mechanism was the hydrogen atom transfer from the catecholic ring. The computed kinetic constants revealed that, in order to obtain reliable results, it is important to consider all the species present in water solution derived from acid–base equilibria. From the present investigation, it emerges that at physiological pH (7.4), the scavenging activity of higenamine against the •OOH radical is higher than that of Trolox, chosen as a reference antioxidant. Furthermore, higenamine results to be more efficient for that purpose than melatonin and caffeine, whose protective action against oxidative stress is frequently associated with their reactive oxygen species (ROS) scavenging activity.