Density functional theory (B3LYP) was employed to examine the hydrolysis of the canonical 2'-deoxynucleotides in varied environments (gas phase or water) using different computational models for the sugar residue (methyl or phosphate group at C5') and nucleophile (water activated through full or partial proton abstraction). Regardless of the degree of nucleophile activation, our results show that key geometrical parameters along the reaction pathway are notably altered upon direct inclusion of solvent effects in the optimization routine, which leads to significant changes in the reaction energetics and better agreement with experiment. Therefore, despite the wide use of gas-phase calculations in the literature, small model computational work, as well as large-scale enzyme models, that strive to understand nucleotide deglycosylation must adequately describe the environment. Alternatively, although inclusion of the phosphate group at C5' also affects the geometries of important stationary points, the effects cancel to yield unchanged deglycosylation barriers, and therefore smaller computational models can be used to estimate the energy associated with nucleotide deglycosylation, with the 5' phosphate group included if full (geometric) details of the reaction are desired. Hydrogen-bonding interactions with the nucleobase can significantly reduce the barrier to deglycosylation, which supports suggestions that discrete hydrogen-bonding interactions with active-site amino acid residues can play a significant role in enzyme-catalyzed nucleobase excision. Taken together with previous studies, the present work provides vital clues about the components that must be included in future studies of the deglycosylation of isolated noncanonical nucleotides, as well as the corresponding enzyme-catalyzed reactions.