We investigate solvent effects in the hydrodeoxygenation of 4-propylguaiacol (4PG, 166 amu), a key lignin-derived monomer, over Ru/C catalyst by combined operando synchrotron photoelectron photoion coincidence (PEPICO) spectroscopy and molecular dynamics simulations. With and without isooctane co-feeding, ring-hydrogenated 2-methoxy-4-propylcyclohexanol (172 amu) is the first product, due to the favorable flat adsorption configuration of 4PG on the catalyst surface. In contrast, tetrahydrofuran (THF)—a polar aprotic solvent that is representative of those used for lignin solubilization and upgrading—strongly coordinates to the catalyst surface at the oxygen atom. This induces a local steric hindrance, blocking the flat adsorption of 4PG more effectively, as it needs more Ru sites than the tilted adsorption configuration revealed by molecular dynamics simulations. Therefore, THF suppresses benzene ring hydrogenation, favoring a demethoxylation route that yields 4-propylphenol (136 amu), followed by dehydroxylation to propylbenzene (120 amu). Solvent selection may provide new avenues for controlling catalytic selectivity.