Pd-doped propyl sulfonic acid-functionalized hollow nanospheres proved to be efficient bifunctionalized catalysts for the one-pot synthesis of methyl isobutyl ketone (MIBK) from acetone and hydrogen in liquid phase. These hollow nanospheres exhibited a higher activity than their bulk mesoporous counterparts (SBA-15 or FDU-12), mainly due to the short diffusion resistance of hollow nanospheres. Hollow nanospheres with silica frameworks showed higher activity and selectivity for MIBK than those with ethane-bridged frameworks, suggesting that hollow nanospheres with hydrophilic surface properties favor the formation of MIBK. This is probably due to the increased affinity of the hydrophilic surface towards acetone and its decreased affinity towards MIBK, which precludes deep condensation of MIBK with acetone. Under optimal conditions, up to 90 % selectivity for MIBK can be obtained with conversions of acetone as high as 43 %. This result is among the best reported so far for mesoporous silica-based catalysts. The control/fine-tuning of morphology and surface properties provides an efficient strategy for improving the catalytic performance of solid catalysts.