In the frame of DFT paradigms, the adsorption of 2-methyl-3-butyn-2-ol (MBY) and 2-methyl-3-buten-2-ol (MBE) on a Pd-30 cluster, including both {100} and {111} faces, was studied along with the pathways involved in the hydrogenation, taking place on plane and low coordination (corner/edge) sites of given MBY/Pd-30 and MBE/Pd-30 surface configurations. The calculated energetics, further validated by gas-phase and water-assisted gas-phase MBY and MBE hydrogenation, performed on well-defined size and shape-controlled Pd nanoparticles supported on SiO2, were able to explain the origin of the structure sensitivity and the high selectivity characterizing the title reaction when occurring in aqueous solution. The C C moiety of the MBY surface species indeed seemed to be mostly activated by plane sites instead of corner/edge atoms, whereas the MBE species appeared to have a different behavior, with their C=C moieties typically being activated by low coordination sites. DFT studies excluded that the overhydrogenation paths could be affected by the site topologies; hence, the role of plane, edge, or corner atoms should not be influential in setting the surface reaction mechanism, which as a consequence could be controlled by the adsorption energy, actually distinguished by different values on sites of different topology. The role of water in the selectivity to MBE, which characterizes the catalytic overhydrogenation of MBY on I'd nanoparticles, was also inferred.