Catalytic removal of oxygen from biomass by hydrodeoxygenation (HDO) as a promising process has been pursued for efficient utilization of biomass resources. Here we report a self-support semi-hollow carbon nanospheres (SHCN) supported palladium (Pd) catalyst for vanillin HDO under mild conditions. The shell-void-core structure of carbon nanospheres originates from the modulation of growth kinetics of resorcinol/formaldehyde resin precursors by a given volume of acetone. Notably, 0.5%Pd/SHCN-60 (acetone of 60 mL) catalyst exhibits >99.9% of vanillin conversion and creosol selectivity under 25 °C and 0.1 MPa of H2. The good catalytic results can derive from the self-support hollow carbon support and active metallic Pd. Raman results show that 0.5%Pd/SHCN-60 possesses the most abundant defect carbon (AD1/AG = 2.02), which leads to the small particle size (mean size of 2.9 nm) and well dispersion (29.5%) of Pd. Higher H2-desorption temperature (∼440 °C) of 0.5%Pd/SHCN-60 by H2-TPD demonstrates the strong interaction of Pd-defect carbon. The strong interaction favors the hydrogen storage and activation of substrates under low pressure of H2 and reaction temperature, which improves the hydrogenation and hydrogenolysis. Additionally, the contribution of unique core structure to support the shell to enhance mechanical stability leads to intact morphology of catalyst and stable catalytic performance after reused six times. This investigation can provide a design idea of carbon-based catalysts for mild HDO.