Sugar alcohols are applied in the food, pharmaceutical, polymer, and fuel industries and are commonly obtained by reduction of the corresponding saccharides. In view of the rarity of some sugar substrates, epimerization of a readily available monosaccharide has been proposed as a solution, but an efficient catalytic system has not yet been identified. Herein, a molybdenum heteropolyacid-based catalyst is developed to transform glucose, arabinose, and xylose into less-abundant mannose, ribose, and lyxose, respectively. Adsorption of molybdic acid onto activated carbon followed by ion exchange to the cesium form limits leaching of the active phase, which greatly improves the catalyst stability over 24 h on stream. The hydrogenation of mixtures of epimers is studied over ruthenium catalysts, and it is found that the precursor to the desired polyol is advantageously converted with faster kinetics. This is explained by density functional theory on the basis of its more favorable adsorption on the metal surface and the lower energy barrier for the addition of a hydrogen atom to the primary carbon atom. Finally, different designs for a continuous process for the conversion of glucose into mannitol are studied, and it is uncovered that two reactors in series with one containing the epimerization catalyst and the other containing a mixture of the epimerization and hydrogenation catalysts increases the mannitol/sorbitol ratio to 1.5 from 1 for a single mixed-bed reactor. This opens a prospective route to the efficient valorization of renewables to added-value chemicals.