Context <p>Inotilone, a bioactive phenolic compound isolated from medicinal fungi (<i>Phellinus</i> and <i>Inonotus</i>), exhibits promising antioxidant activity. However, its molecular mechanism remains unclear. This study investigates its radical scavenging behavior in aqueous and lipid-like environments using quantum chemical approaches. Thermodynamic results identify hydroxyl groups as the most reactive sites, while deprotonation is highly favored in water, leading to dominance of the monoanionic form at physiological pH. Kinetic analysis reveals that the antioxidant activity in aqueous solution is governed by the single electron transfer pathway of deprotonated species, yielding high-rate constants (<i>k</i>_{<i>o</i>verall} = 7.27 × 10⁶&#xa0;M⁻¹&#xa0;s⁻¹), significantly exceeding that of Trolox. In contrast, in non-polar media, the reaction proceeds mainly via formal hydrogen atom transfer with much lower efficiency, highlighting strong solvent-dependent behavior. </p> Methods <p>Density functional theory calculations were performed at the M06-2X/6–311 +  + G(d,p) level using the SMD solvation model for water and pentyl ethanoate. Thermodynamic descriptors (BDE, IP, PA) were calculated to evaluate fHAT, SET-PT, and SPLET mechanisms. Reaction kinetics with the HOO• radical were investigated using the QM-ORSA protocol to obtain activation free energies and rate constants. All calculations were carried out with Gaussian 09, and kinetic parameters were computed using the Eyringpy software.</p>