The antioxidant activity of natural and semi-synthetic depsides and benzofurans—including R-(+)-usnic acid (1), dibenzoyl usnic acid (2), atranorin (3), 2,4-bis(benzoyloxy)atranorin (4), 4-O-methyl atranorin (5), decarboxythamnolic acid (6), thamnolic acid (7), and perlatolic acid (8)—was evaluated in this study. Natural compounds were isolated from selected lichen species, whilst semi-synthetic derivatives were prepared to investigate the influence of esterification and methylation on electronic properties and radical-scavenging capacity. Structural elucidation was performed using NMR spectroscopy and mass spectrometry (MS). Electronic and thermodynamic descriptors, including the bond dissociation energy (BDE) of the most reactive O–H group, HOMO and LUMOr energies, the HOMO–HOMO-1 energy gap (ΔH(H-1)), polarisability, and logP, were calculated and correlated with experimentally determined antioxidant capacity using the TEAC assay. Multivariate partial least squares (PLS-1) analysis identified ΔH(H-1) and LUMOr as the primary determinants of antioxidant activity, with BDE and ΔHf providing complementary contributions. Perlatolic acid (8) exhibited the highest radical-scavenging capacity (TEAC = 2.7), whereas R-(+)-usnic acid (1) and dibenzoyl usnic acid (2) were the least active compounds (TEAC ≈ 0.1). Antioxidant activity was found not to correlate with the number of hydroxyl groups, but rather to be governed by electronic redistribution, conjugation effects, and substituent modulation. Exclusion of the outlier decarboxythamnolic acid (6) improved model performance, explaining 79.8% of the variance in TEAC values (R2Y), with strong predictive ability (Q2 = 0.724) using a single latent variable. Overall, these findings provide a robust basis for the prediction and rational design of new antioxidant compounds, highlighting the relevance of lichen-derived metabolites as structurally stable scaffolds with potential applications in pharmaceutical and nutraceutical development. Keywords: lichen-derived depsides; QSAR; electronic descriptors; phenoxyl radical; PLS-1; TEAC assay.