Depsidones are secondary metabolites in lichens with a range of potential health benefits. Among others, these compounds are believed to exhibit high hydroxyl radical and superoxide scavenging abilities, warranting a detailed investigation of their antioxidant properties. In this study, the radical scavenging activity of natural depsidones from Ramalina lichenized fungi was investigated in silico. Calculations of the thermodynamic parameters suggested that the main radical scavenging pathway follows the formal hydrogen transfer (FHT) mechanism; however, unexpectedly low rate constants were found in the CH₃OO^• scavenging reaction. Establishing that the depsidones are mostly ionized in an aqueous environment suggested that the single-electron transfer (SET) mechanism should not be ruled out. Consistently, depsidones were revealed to be excellent HO^• and O₂^•– scavengers in aqueous solutions (k = 4.60 × 10⁵ – 8.60 × 10⁹ M^–1 s^–1 and k = 2.60 × 10⁸ – 8.30 × 10⁹ M^–1 s^–1, respectively) following the sequential proton loss electron transfer (SPLET) mechanism. These results suggest that natural fungal depsidones are potent hydroxyl and superoxide radical scavengers in aqueous solutions.