Deglycosylation of nucleotides occurs during many essential biological processes, including DNA repair, and is initiated by a variety of nucleophiles. In the present work, density functional theory (B3LYP) was used to investigate the thermodynamics and kinetics of the glycosidic bond cleavage reaction in the model nucleoside forms of guanine and its major oxidation product, 8-oxoguanine. Base excision facilitated by four different nucleophiles (hydroxyl anion (fully activated water), formate-water complex (partially activated water), lysine, and proline) was considered, which spans nucleophiles involved in a collection of spontaneous and enzyme-catalyzed processes. Because some enzymes that catalyze deglycosylation can accommodate more than one orientation of the base with respect to the sugar moiety, the effects of the (anti/syn) base orientation on the barrier height were also considered. We find that the nucleophile has a very large effect on the overall (gas-phase) reaction energetics. Although this effect decreases in different (polar) environments, the nucleophile has the greatest influence on the overall reaction as compared to whether the base is damaged or to the base orientation. Furthermore, the effects are significant in environments that most closely resemble (nonpolar) enzymatic active sites. Our results provide a greater understanding of the relative effects of the nucleophile, damage to the nucleobase, and the nucleobase orientation with respect to the sugar moiety on the deglycosylation pathway, which provide qualitative explanations for relative base excision rates observed in some biological systems.