Comprehensive mechanistic insights into the aqueous-phase hydrogenolysis of glycerol by the ReO x -Ir catalyst were obtained by combining density functional theory (DFT) calculations with batch reaction experiments and detailed characterization of the catalysts using X-ray diffraction, X-ray photoelectron spectroscopy, and Fourier transform infrared techniques. The role and contribution of the aqueous acidic reaction medium were investigated using NMR relaxometry studies complemented with molecular dynamics and DFT calculations. At higher glycerol concentration, the enhanced competitive interaction of glycerol with the catalyst improved the conversion of glycerol. Sulfuric acid increased the concentration of glycerol within the pores of the catalyst and enhanced the propensity for dissociative adsorption of glycerol on the catalyst, explaining the promotional effect of acid during hydrogenolysis. Partially reduced and dispersed Brønsted acidic ReO x clusters on metallic Ir nanoparticles facilitated dissociative attachment of glycerol and preferential formation of the primary propoxide. The formation of the dominant product, 1,3-propanediol (1,3-PDO), results from the selective removal of the secondary hydroxyl of glycerol, with a comparatively low activation barrier of 123.3 kJ mol -1 in the solid Brønsted acid-catalyzed protonation-dehydration mechanism or 165.2 kJ mol -1 in the direct dehydroxylation mechanism. The formation of 1-propanol (1-PO) is likely to follow a successive dehydroxylation pathway in the early stages of the reaction. Although 1,3-PDO is less reactive than 1,2-propanediol (1,2-PDO), it preferentially adsorbs on the catalyst in a mixture containing glycerol to form 1-PO. The thermodynamically favorable pathway involving dehydrogenation, dehydroxylation, and hydrogenation elementary steps led to the dominant production of 1,2-PDO on pure Ir catalyst with a high C-O bond cleavage barrier of 207.4 kJ mol -1 . The optimum ReO x -Ir catalyst with an Ir/Re ratio of 1 exploits the synergy of the sites of both the components. The detailed insights presented here would guide the rational selection of catalysts for the hydrogenolysis of polyols and the optimization of reaction parameters. © 2018 American Chemical Society.