Efficient depolymerization methods are critical to the sustainable production of fuels and chemicals from biomass. Ligand-controlled selective C(sp3)–O and Ar–C(sp3) cleavages of β-O-4 lignin model compounds were realized with vanadium catalysts under redox-neutral conditions or air atmosphere. To clarify the mechanism and the origin of selectivity, a joint theoretical and experimental study was performed herein. First, with the aid of density functional theory (DFT) calculations, an updated mechanism involving VV, VIV, and VIII complexes was discovered for the C(sp3)–O cleavage process catalyzed by the Schiff base vanadium complexes with an overall free energy barrier of 34.9 kcal/mol. Meanwhile, a detailed catalytic cycle involving novel stepwise O–O/Ar–C(sp3) cleavage was clarified for the Ar–C(sp3) cleavage process catalyzed by the bis(8-oxyquinolate) coordinated vanadium complexes, having an overall free energy barrier of 28.8 kcal/mol. Further analysis based on the energetic span model revealed that...