Abstract: Lignin is the most abundant natural aromatic polymer, and its catalytically depolymerized products can serve as precursors for high-value chemicals and biojet fuel. However, the mechanism of lignin solubilization and its interfacial interactions with catalysts remain unclear, limiting the development of highly efficient catalytic systems. In this study, atomic force microscopy is innovatively employed to quantify intermolecular forces within lignin and at the lignin-catalyst interface, establishing a correlation between lignin dissolution behavior and catalytic depolymerization performance. Lignin fractions with similar molecular weights but differing polarities were obtained via ultrafiltration and solvent fractionation, and their dissolution and depolymerization behaviors were investigated using molecular dynamics simulations. The results show that the intermolecular force of the ethanol-soluble AL10-F1 fraction in ethanol is −0.036 mN/m, and the monophenol yield obtained through catalytic depolymerization reaches 16.13%, while the intermolecular force of the ethanol-insoluble AL10-F2 component was −1.009 mN/m, with a monophenol yield of only 11.98%. A strong negative correlation was observed between the intermolecular forces of the lignin and the results of catalytic depolymerization. Molecular dynamics simulations confirmed that the AL10-F1 molecule has an extended conformation, high solvent accessibility, and stronger interactions with the catalyst (−92.2 μN/m) , which facilitates adsorption and the catalytic reaction. The technique for quantifying intermolecular forces provides a theoretical foundation and technical support for the development of lignin depolymerization solvents and catalyst design.